A review of 1H MR spectroscopy findings in Alzheimer's disease

Hydrogen-1 MR spectroscopy (MRS) studies demonstrate metabolic differences between patients who have Alzheimer's disease (AD) and cognitive normal age-matched controls. Clinical MRS also shows regional variations in metabolites between patients who have AD and those who have other dementias. Single-voxel and volumetric standard MRS techniques and automated data processing software are available for clinical MR scanners. Improvements in specificity and sensitivity of AD diagnosis, using MRS techniques as an adjunct to clinical imaging, are under evaluation. Multiparametric data analyses show, however, that metabolite changes correlate with in-vitro, postmortem, and metabolic changes and to changes in or predictions of cognitive scores.     

An improved methodology for modeling neurobehavioral late-effects of radiotherapy in pediatric brain tumors

BACKGROUND: Technical advances in radiation oncology provide new opportunities to study neurobehavioral outcomes of radiation therapy (RT) in children treated for brain tumors. METHODS: In this study, we describe an approach to modeling late-effects using integral biologically effective dose (IBED) combined with improved measurement of critical neuropsychological functions. RESULTS: IBED was found to provide more differentiated information about dose distribution than prescribed dose in five subjects treated for brain tumors. Furthermore, IBED was more closely related than was prescribed dose to specific changes in Attention 2-3 years post-RT. CONCLUSIONS: Results support the feasibility of this methodology as well as promising preliminary evidence of the relationship of IBED to the construct of Attention. Improved modeling could lead to more refined radiation therapy protocols that preserve critical neuropsychological functions and also provide new insights into the treatment of neurobehavioral sequelae.     

Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using a multimedia training video and CD-ROM we developed after a two-step validation process. We hypothesized that use of CD-ROM interactive training will lead to reliable and valid performance of the neurologic examination by both pediatric neurologists and nonpediatric neurologists. All examiners were asked to take one of six interobserver variability tests found on the CD-ROM on two occasions. In the first interobserver variability evaluation, 89% (531 of 594) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the two items that had a 60% correct rate, the correct response rate rose to 93% (114 of 123). In the second interobserver variability evaluation, 88% (493 of 560) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the four items that had a 70% correct rate, the correct response rate rose to 96% (104 of 108). Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children. It provides an effective means to evaluate interobserver variability, offers a route for feedback, and creates an opportunity to reevaluate variability, both immediately and at periodic intervals.     

The Pediatric Investigators Collaborative Network on Infections in Canada study of predictors of hospitalization for respiratory syncytial virus infection for infants born at 33 through 35 completed weeks of gestation

BACKGROUND: Infants born at 33 through 35 completed weeks of gestation (33-35GA) are at risk for severe respiratory syncytial virus (RSV) infection, and palivizumab prophylaxis lowers hospitalizations for RSV infection by as much as 80%. The 33-35GA cohort comprises 3-5% of annual births; thus expert panels recommend limiting prophylaxis to situations in which frequency or health care impact of RSV infection is high. This study sought to identify independent risk factors for hospitalization for RSV infection. METHODS: This was a multicenter, prospective, observational cohort study of 33-35GA infants followed through their first RSV season (2001/2002 or 2002/2003). Baseline data were collected by interview with parents and review of medical records. Respiratory tract illnesses were identified by monthly phone calls, and medical records were reviewed for emergency room visits or hospitalizations. Risk factors were determined by stepwise logistic regression. RESULTS: Of 1,860 enrolled subjects, 1,832 (98.5%) were followed for at least 1 month, and 1,760 (94.6%) completed all follow-ups. Of 140 (7.6%) subjects hospitalized for respiratory tract illnesses, 66 infants had proven RSV infection. Independent predictors for hospitalization for RSV infection were: day-care attendance (odds ratio, 12.32; 95% confidence interval, 2.56, 59.34); November through January birth (odds ratio, 4.89; 95% confidence interval, 2.57, 9.29); preschool age sibling(s) (odds ratio, 2.76; 95% confidence interval, 1.51, 5.03); birth weight <10th percentile (odds ratio, 2.19; 95% confidence interval, 1.14, 4.22); male gender (odds ratio, 1.91; 95% confidence interval, 1.10, 3.31); > or = 2 smokers in the home (odds ratio, 1.87; 95% confidence interval, 1.07, 3.26); and households with >5 people, counting the subject (odds ratio, 1.79; 95% confidence interval, 1.02, 3.16). Family history of eczema (odds ratio, 0.42; 95% confidence interval, 0.18, 0.996) was protective. CONCLUSIONS: Specific host/environmental factors can be used to identify which 33-35GA infants are at greatest risk of hospitalization for RSV infection and likely to benefit from palivizumab prophylaxis.     

Cerebrospinal fluid rhinorrhea after thermometer insertion through the nose

Cerebrospinal fluid (CSF) rhinorrhea is a rare clinical condition. Most leaks either are caused by traumatic head injury or are a complication of surgical procedures on the base of the skull. CSF rhinorrhea from nasal tube placement has been reported previously. We report a case of nasal thermometer placement during anesthesia complicated by a CSF leakage. We reemphasize that any material--including thermometers, nasogastric tubes, and endotracheal tubes--should be directed posteriorly after introduction into the external naris.     

Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor

Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy.     

Brca1 inactivation induces p27(Kip1)-dependent cell cycle arrest and delayed development in the mouse mammary gland

One common characteristic of breast cancers arising in carriers of the predisposition gene BRCA1 is a loss of expression of the CDK inhibitor p27(Kip1) (p27), suggesting that p27 interacts epistatically with BRCA1. To investigate this relationship, we examined expression of p27 in mice expressing a dominant negative allele of Brca1 (MMTV-trBr) in the mammary gland. While these mice rarely develop tumors, they showed a 50% increase in p27 protein and a delay in mammary gland development associated with reduced proliferation. In contrast, on a p27 heterozygote background, MMTV-trBrca1 mice showed an increase in S phase cells, and normal mammary development. p27 was the only protein in the cyclin-cyclin-dependent kinase network to show altered expression, suggesting that it may be a central mediator of cell cycle arrest in response to loss of function of BRCA1. Furthermore, in human mammary epithelial MCF7 cells expressing BRCA1-specific RNAi and in the BRCA1-deficient human tumor cell line HCC1937, p27 is elevated at the mRNA level compared to cells expressing wild-type BRCA1. We hypothesize that disruption of BRCA1 induces an increase in p27 that inhibits proliferation. Accordingly, reduction in p27 expression leads to enhancement of cellular proliferation in the absence of BRCA1.