Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy.

Key Points Question How does augmentation with a deep learning segmentation model influence the performance of clinicians in identifying intracranial aneurysms from computed tomographic angiography examinations? Findings In this diagnostic study of intracranial aneurysms, a test set of 115 examinations was reviewed once with model augmentation and once without in a randomized order by 8 clinicians. The clinicians showed significant increases in sensitivity, accuracy, and interrater agreement when augmented with neural network model–generated segmentations. Meaning This study suggests that the performance of clinicians in the detection of intracranial aneurysms can be improved by augmentation using deep learning segmentation models.

Object. The objective of this study was to compare the accuracy of 3 methods of ventricular catheter placement during CSF shunt operations: the freehand technique using surface anatomy, ultrasonic guidance, and stereotactic neuronavigation.Methods. This retrospective cohort study included all patients from a single institution who underwent a ven tricular CSF shunting procedure in which a new ventricular catheter was placed between January 2005 and March 2010. Data abstracted for each patient included age, sex, diagnosis, method of ventricular catheter placement, site and side of ventricular catheter placement, Evans ratio, and bifrontal ventricular span. Postoperative radiographic stud ies were reviewed for accuracy of ventricular catheter placement. Medical records were also reviewed for evidence of shunt failure requiring revision through December 2011. Statistical analysis was then performed comparing the 3 methods of ventricular catheter placement and to determine risk factors for inaccurate placement.Results. There were 249 patients included in the study; 170 ventricular catheters were freehand passed, 51 were placed using stereotactic neuronavigation, and 28 were placed under intraoperative ultrasonic guidance. There was a statistically significant difference between freehand catheters and stereotactic-guided catheters (p < 0.001), as well as between freehand catheters and ultrasound-guided catheters (p < 0.001). The only risk factor for inaccurate place ment identified in this study was use of the freehand technique. The use of stereotactic neuronavigation and ultrasonic guidance reduced proximal shunt failure rates (p < 0.05) in comparison with a freehand technique.Conclusions. Stereotactic-and ultrasound-guided ventricular catheter placements are significantly more accu rate than freehand placement, and the use of these intraoperative guidance techniques reduced proximal shunt failure in this study.

Breast cancer commonly causes osteolytic metastases in bone, a process that is dependent on tumor-stromal interaction. Proteases play an important role in modulating tumorstromal interactions in a manner that favors tumor establishment and progression. Whereas several studies have examined the role of proteases in modulating the bone microenvironment, little is currently known about their role in tumor-bone interaction during osteolytic metastasis. In cancer-induced osteolytic lesions, cleavage of receptor activator of nuclear factor-KB ligand (RANKL) to a soluble version (sRANKL) is critical for widespread osteoclast activation. Using a mouse model that mimics osteolytic changes associated with breast cancer-induced bone metastases, we identified cathepsin G, cathepsin K, matrix metalloproteinase (MMP)-9, and MMP13 to be proteases that are up-regulated at the tumor-bone interface using comparative cDNA microarray analysis and quantitative reverse transcription-PCR. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of RANKL, generating active sRANKL that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G at the tumor-bone interface seems to be osteoclasts that up-regulate production of cathepsin G via interaction with tumor cells. Furthermore, we showed that in vitro osteoclastogenesis is reduced by inhibition of cathepsin G in a coculture model and that in vivo inhibition of cathepsin G reduces mammary tumor-induced osteolysis. Together, our data indicate that cathepsin G activity at the tumor-bone interface plays an important role in mammary tumor-induced osteolysis and suggest that cathepsin G is a potentially novel therapeutic target in the treatment of breast cancer bone metastasis. [Cancer Res 2008;68(14):5803-11]

Chromophores with a benzylidene imidazolidinone core define the emission profile of commonly used biomarkers such as the green fluorescent protein (GFP) and its analogues. In this communication, artificially engineered porous scaffolds have been shown to mimic the protein β-barrel structure, maintaining green fluorescence response and conformational rigidity of GFP-like chromophores. In particular, we demonstrated that the emission maximum in our artificial scaffolds is similar to those observed in the spectra of the natural GFP-based systems. To correlate the fluorescence response with a structure and perform a comprehensive analysis of the prepared photoluminescent scaffolds, (13)C cross-polarization magic angle spinning solid-state (CP-MAS) NMR spectroscopy, powder and single-crystal X-ray diffraction, and time-resolved fluorescence spectroscopy were employed. Quadrupolar spin-echo solid-state (2)H NMR spectroscopy, in combination with theoretical calculations, was implemented to probe low-frequency vibrational dynamics of the confined chromophores, demonstrating conformational restrictions imposed on the coordinatively trapped chromophores. Because of possible tunability of the introduced scaffolds, these studies could foreshadow utilization of the presented approach toward directing a fluorescence response in artificial GFP mimics, modulating a protein microenvironment, and controlling nonradiative pathways through chromophore dynamics.

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1. Pig intestinal sucrase and maltase activities increase markedly, and lactase activity decreases, during the second week of post‐natal life. Correlations noted between the time course describing these changes and that found previously to describe a decline in the ability of the pig intestine to take up macromolecules suggest that both events are subject to the same type of developmental control. 2. Injection of epidermal growth factor (EGF) into 3‐day‐old piglets increase sucrase and maltase activities measured 3 days later. These increases, which are not seen when measuring other hydrolase enzymes, are confined to the mid and distal regions of the small intestine. 3. Dexamethasone injected into 3‐day‐old piglets inhibits lactase and, on occasion, sucrase activities without affecting other intestinal hydrolases. Significant increases in sucrase and maltase activities also occur in distal intestine following injection of EGF plus dexamethasone into 3‐day‐old pigs. 4. Cytochemical analysis shows EGF effects on sucrase and maltase activities to be exerted in crypt and basal villus enterocytes produced post‐natally. Dexamethasone inhibits lactase activity mainly by acting on mid and upper villus enterocytes produced before birth. 5. EGF appears to increase sucrase and maltase activities by extending the time during which young enterocytes continue to accumulate these enzymes in their brush‐border membranes. Dexamethasone appears to cause a more fundamental change in the biochemistry of older enterocytes. accompanied by an increasing ability of these cells to transport neutral amino acids through a sodium‐dependent mechanism (see James, Smith, Tivey & Wilson, 1987a).

Alterations in blood flow and consistency, but not vessel injury, appear associated with symptomatic thrombosis following placement of PICCs in neurological intensive care patients. Mannitol use and placement in a paretic arm are potentially modifiable risk factors. Given the high incidence rate of symptomatic thrombosis, future studies should focus on comparing cumulative complications of centrally inserted venous catheters and PICCs in intensive care patients.