Incomplete rescue of cystic fibrosis transmembrane conductance regulator deficient mice by the human CFTR cDNA

We have used a mouse model to study the ability of human CFTR to correct the defect in mice deficient of the endogenous protein. In this model, expression of the endogenous Cftr gene was disrupted and replaced with a human CFTR cDNA by a gene targeted 'knock-in' event. Animals homozygous for the gene replacement failed to show neither improved intestinal pathology nor survival when compared to mice completely lacking CFTR. RNA analyses showed that the human CFTR sequence was transcribed from the targeted allele in the respiratory and intestinal epithelial cells. Furthermore, in vivo potential difference measurements showed that basal CFTR chloride channel activity was present in the apical membranes of both nasal and rectal epithelial cells in all homozygous knock-in animals examined. Ussing chamber studies showed, however, that the cAMP-mediated chloride channel function was impaired in the intestinal tract among the majority of homozygous knock-in animals. Hence, failure to correct the intestinal pathology associated with loss of endogenous CFTR was related to inefficient functional expression of the human protein in mice. These results emphasize the need to understand the tissue- specific expression and regulation of CFTR function when animal models are used in gene therapy studies.      

Mixture models of serum iron measures in population screening for hemochromatosis and iron overload

Homozygosity for the C282Y mutation of the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. The authors describe and apply methodology developed for the analysis of phenotypic and genotypic data from 46,136 non-Hispanic Caucasians, a subset of the multi-ethnic cohort enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. For analysis of the distribution of transferrin saturation (TS), mixtures of normal distributions were considered and the expectation-maximization (EM) algorithm was applied for parameter estimation. Maximized log-likelihoods were compared, and significance was assessed by resampling. Sensitivity, specificity, and predictive values from the modeled subpopulations were compared with the actual observed genotypes for C282Y and H63D mutations in the HFE gene. A strong association between HFE genotype and TS subpopulations was found in these data collected from different geographic regions, confirming the external validity of the statistical approach when applied to population-based data. It was concluded that mixture modeling of phenotypic data may provide a clinical guide for screening with gender-specific thresholds to identify potential samples for genetic testing.     

A systematic review on the utility of ultrasonography in the diagnosis of testicular torsion in acute scrotum patients

IntroductionUltrasound is a valuable tool in establishing the cause of acute scrotum pain. However, its role in testicular torsion (TT) detection remains controversial. This review aims integrate pre-existing data to assess the value of B-mode and colour Doppler ultrasound (CDS) features combined in the detection of TT in acute scrotum pain patients of all ages.MethodsA search through electronic databases, grey literature and hand searching using specific search terms was conducted to identify relevant literature. Search results were subjected to a three-step selection process to ensure the inclusion criteria of this review were met. Statistical data pertaining to the accuracy, sensitivity, and specificity of the B-mode, CDS and combined B-mode CDS features were extracted. These results subsequently underwent a narrative analysis.ResultsFive studies met the inclusion criteria. A variety of B-mode features were identified. Most studies showed that reliance on CDS alone can be prone to false-negative results. The combination of B-mode and CDS features were found to increase the overall sensitivity of ultrasound towards TT (up to 100% in 3 studies). All studies recommended correlation with clinical examination findings. Several limitations in methodology of the included studies were noted: small sample populations and lack of information on the experience of ultrasound practitioners. This highlighted the need for a primary study with a larger sample population to validate the findings of this review.ConclusionThe combination of B-mode and CDS ultrasound is a useful and reliable triage tool in the detection of TT, particularly in equivocal or low suspicion cases but its findings should always be adjunct with clinical examination. Nevertheless, it is noted that appropriate service level agreements, pathways, and training are key factors in ensuring effectiveness of the process.Implications for practiceDedicated training and appropriate departmental protocol are key in ensuring accurate diagnosis across all levels of practice.     

原发性单侧症状帕金森病磁共振氢质子谱研究

目的:探讨磁共振氢质子谱(1H-MRS)对原发性单侧起病帕金森病的诊断价值。方法:未经治疗的原发单侧症状PD患者50例为PD组,健康人42名为对照组。两组分别予以双侧壳核MRS检查,由仪器自带软件自动计算得双侧壳核代谢物比值:NAA/Cr,Cho/Cr,NAA/Cho。结果:PD组患者其症状对侧壳核NAA/cr比值分别较同侧及健康对照组双侧壳核相应比值均值明显下降(分别为1.23±0.22,1.38±0.33,1.33±0.16;t=2.616,P=0.01和t=2.324,P=0.02),而其NAA/Cho、Cho/Cr比值较同侧及对照组相应比值均值无显著差异。症状同侧壳核NAA/cr、NAA/Cho、Cho/Cr较对照组无明显差异。结论:原发性单侧症状PD其症状的对侧壳核早期就可能存在神经元的缺失或胶质增生,提示壳核磁共振波谱分析可为早期PD的临床诊断提供较为可靠的客观依据。     

Multiple cerebral metastases: detectability with Gd-DTPA-enhanced MR imaging

Sixteen patients with suspected cerebral metastases were studied with magnetic resonance (MR) imaging before and after the intravenous administration of 0.1 mmol/kg of gadolinium diethylenetriaminepenta-acetic acid. The images were interpreted blindly by two neuroradiologists; all clinical, radiologic (computed tomographic and MR imaging), and pathologic data were reviewed to arrive at a final "best diagnosis," which was then compared with the prior blinded interpretations. Of seven patients found to have multiple metastases, six (86%) had at least one tumor nodule depicted by postinfusion MR imaging that was missed by one or both observers on review of preinfusion images alone. Lesions missed on preinfusion studies were usually small nodules hidden by or not detected next to regions of high-signal edema thought to be related to the adjacent tumor nodule. The authors believe that contrast enhancement improves detection of metastatic foci with MR imaging and that the findings indicate broader implications for the detection of multiple lesions from other causes.     

Interventional radiology in the airway in children

Interventional procedures in the airway can be performed in interventional radiology suites or the operating room, by radiologists or other specialists. The most common therapeutic interventions carried out by radiologists are balloon dilatation, stenting, and the treatment of certain airway fistulas. These operations can be very challenging for anesthetists in terms of planning, airway management, the identification and treatment of procedural complications and postoperative care. In particular, a multidisciplinary approach to decision‐making and planning is important to obtain the best results.     

Digital radiography of subtle pulmonary abnormalities: an ROC study of the effect of pixel size on observer performance

Forty conventional radiographs with examples of mild interstitial infiltrates and subtle pneumothoraces and 40 normal studies of the chest were selected and digitized, with pixel sizes of 1.0, 0.5, 0.2, and 0.1 mm. Observer performance tests were carried out using receiver operating characteristic analysis. Conventional radiographs and digitized images were compared. The results indicate that, in such cases, diagnostic accuracy increases significantly as the pixel size is reduced, at least to the 0.1-mm level. We conclude that, for digital systems using screen-film or similar image receptors, use of a pixel size substantially larger than 0.1 mm may result in some loss of diagnostic accuracy.     

Have Levels of Evidence Improved the Quality of Orthopaedic Research?

Background

Since 2003 many orthopaedic journals have adopted grading systems for levels of evidence (LOE). It is unclear if the quality of orthopaedic literature has changed since LOE was introduced.

Questions/purposes

We asked three questions: (1) Have the overall number and proportion of Level I and II studies increased in the orthopaedic literature since the introduction of LOE? (2) Is a similar pattern seen in individual orthopaedic subspecialty journals? (3) What is the interobserver reliability of grading LOE?

Methods

We assigned LOE to therapeutic studies published in 2000, 2005, and 2010 in eight major orthopaedic subspecialty journals. Number and proportion of Level I and II publications were determined. Data were evaluated using log-linear models. Twenty-six reviewers (13 residents and 13 attendings) graded LOE of 20 blinded therapeutic articles from the Journal of Bone and Joint Surgery for 2009. Interobserver agreement relative to the Journal of Bone and Joint Surgery was assessed using a weighted kappa.

Results

The total number of Level I and II publications in subspecialty journals increased from 150 in 2000 to 239 in 2010. The proportion of high-quality publications increased with time (p < 0.001). All subspecialty journals other than the Journal of Pediatric Orthopaedics and the Journal of Orthopaedic Trauma showed a similar behavior. Average weighted kappa was 0.791 for residents and 0.842 for faculty (p = 0.209).

Conclusions

The number and proportion of Level I and II publications have increased. LOE can be graded reliably with high interobserver agreement. The number and proportion of high-level studies should continue to increase.