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91.
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Kamal KE Gadalla Mark ES Bailey Rosemary C Spike Paul D Ross Kenton T Woodard Sahana Nagabhushan Kalburgi Lavanya Bachaboina Jie V Deng Anne E West R Jude Samulski Steven J Gray Stuart R Cobb 《Molecular therapy》2013,21(1):18-30
Typical Rett syndrome (RTT) is a pediatric disorder caused by loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. The demonstrated reversibility of RTT-like phenotypes in mice suggests that MECP2 gene replacement is a potential therapeutic option in patients. We report improvements in survival and phenotypic severity in Mecp2-null male mice after neonatal intracranial delivery of a single-stranded (ss) AAV9/chicken β-actin (CBA)-MECP2 vector. Median survival was 16.6 weeks for MECP2-treated versus 9.3 weeks for green fluorescent protein (GFP)-treated mice. ssAAV9/CBA-MECP2–treated mice also showed significant improvement in the phenotype severity score, in locomotor function, and in exploratory activity, as well as a normalization of neuronal nuclear volume in transduced cells. Wild-type (WT) mice receiving neonatal injections of the same ssAAV9/CBA-MECP2 vector did not show any significant deficits, suggesting a tolerance for modest MeCP2 overexpression. To test a MECP2 gene replacement approach in a manner more relevant for human translation, a self-complementary (sc) adeno-associated virus (AAV) vector designed to drive MeCP2 expression from a fragment of the Mecp2 promoter was injected intravenously (IV) into juvenile (4–5 weeks old) Mecp2-null mice. While the brain transduction efficiency in juvenile mice was low (~2–4% of neurons), modest improvements in survival were still observed. These results support the concept of MECP2 gene therapy for RTT. 相似文献
93.
Preliminary performance of a surgically implanted neuroprosthesis for standing and transfers--where do we stand? 总被引:2,自引:0,他引:2
J A Davis R J Triolo J Uhlir C Bieri L Rohde D Lissy S Kukke 《Journal of rehabilitation research and development》2001,38(6):609-617
This paper describes the preliminary performance of a surgically implanted neuroprosthesis for standing and transfers after spinal cord injury (SCI) in an initial group of 12 volunteers with longstanding paralysis. The CWRU/VA standing neuroprosthesis consists of an 8-channel implanted receiver-stimulator, epimysial and surgically implanted intramuscular electrodes, and a programmable wearable external controller. After reconditioning exercise and rehabilitation with the system, most individuals with paraplegia or low tetraplegia were able to stand, transfer, and release one hand from a support device to manipulate objects in the environment or to perform swing-to ambulation in a walker. The effort and assistance required for transfers were reduced for users with mid-level tetraplegia, although the maneuvers were not independent. Neuroprosthesis users with tetraplegia and paraplegia alike benefited from the improvements in their general health derived from exercise, including reduced risk of decubiti and self-reported modulation of spasticity. Stimulated responses are stable and sufficiently strong for function, and implanted components are reliable with a 90% probability of epimysial electrode survival at 4 years post-implant. The techniques employed are repeatable and teachable, and suitable for multi-center clinical trial. 相似文献
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Nevin T. Wijesekera Giovanni Mauri Sahana Gupta Anna-Maria Belli Isaac T. Manyonda 《Archives of gynecology and obstetrics》2012,286(5):1165-1171
Purpose
To evaluate the technical success of total fibroid clearance at open myomectomy for massive and/or multiple symptomatic fibroids using MR imaging (MRI) as the imaging modality.Methods
The study group comprised 27 women [mean age 37.4?±?6.9?years (range 27–53)] who underwent open myomectomy for the treatment of massive/multiple symptomatic fibroids at our institution between January 2009 and April 2010. Myomectomy was performed with the intention of achieving complete fibroid clearance. Pre- and postmyomectomy MRI was performed to assess changes in uterine volume and fibroid burden. Periprocedural data (including blood loss and complications) and relief of clinical symptoms at follow-up were also recorded.Results
The mean time to MRI and clinical follow-up was 10?months (range 6–15?months). The mean uterine volume premyomectomy was 795?±?580?cc and postmyomectomy was 123?±?70?cc (p?<?0.001). The mean percentage reduction in uterine volume was 80.3?% (range 43.0–98.1?%). Of the 10/27 (37.0?%) women with residual fibroids at follow-up: 7 patients had fibroids measuring up to 1?cc in volume, 3 patients had fibroids measuring up to 6?cc. Postoperative adnexal seromas were observed in 6/27 (22.2?%) patients. The clinical success rates of myomectomy amongst the 22/27 (81?%) responders were: 73?% for menorrhagia, 64?% for pain, and 36–64?% for mass-related symptoms.Conclusions
Using MRI, we have confirmed that open myomectomy can achieve total or near-total fibroid clearance in the majority of patients with massive and/or multiple fibroids. 相似文献96.
Cheung AT Price AR Duong PL Ramanujam S Gut J Larkin EC Chen PC Wilson DM 《Microvascular research》2002,63(3):252-258
Microvascular abnormalities are associated with and causative of the development of end-stage organ complications in adult diabetic patients. Whether the same microvascular abnormalities are present in pediatric patients is not known and has not been studied because of a lack of real-time technology, methodology to study young patients, and availability of an appropriate noninvasive site for in vivo studies. We hypothesized that microvascular abnormalities should be present in pediatric patients despite their young age and the relatively short durations of the disease. In this study, computer-assisted intravital microscopy (CAIM) was adapted to blindly quantify microvascular abnormalities in 12 pediatric type 1 diabetic mellitus (T1DM) patients (ages = 6-16 years; mean +/- SD = 11.42 +/- 3.42; duration since diagnosis = 2-14 years; mean +/- SD = 6.75 +/- 3.79) in vivo, using the microcirculation of the bulbar conjunctiva as a noninvasive site. Microvascular abnormalities, commonly found in adult patients, existed in the conjunctival microcirculation of all pediatric T1DM patients in varying degrees despite their relatively young age. A severity index (SI) was developed to reflect the cumulative severity of the microvascular abnormalities and was computed as the summation of all microvascular abnormalities found in each patient. SI for the 12 T1DM patients (mean +/- SD = 7.42 +/- 1.88; median = 8; mode = 9) differed significantly from that for the nondiabetic controls (mean +/- SD = 0.67 +/- 0.78; median = 0.5; mode = 0; P < 0.0001). In addition, SI correlated with hemoglobin A1c levels (mean +/- SD = 9.18 +/- 1.57) of T1DM patients but did not correlate with the duration of disease since diagnosis of the same patients. This observation raises the possibility that diabetic pathogenesis may precede the onset of overt disease or clinical diagnosis. This study confirms that CAIM may represent the availability of a useful real-time technology to study conjunctival microvascular abnormalities in vascular diseases in juvenile as well as adult patients. 相似文献
97.
Sinha AK Acharya K Bhattacharya S Patra SC Guha M Ray U Ray SB Khan GA Chakraborty K Biswas J Mazumdar S 《Journal of cancer research and clinical oncology》2002,128(12):659-668
PURPOSE: The plasma level of nitric oxide (NO), that has been reported to possess various antineoplastic properties, was found to be diminished due to the impairment of insulin-activated nitric oxide synthase (IANOS) as a result of the appearance of a novel antibody (free light chain of IgG, M(r) 44 kD) against the enzyme in the circulation in various cancers compared to normal control. METHODS: We report here two NO-generating agents, antineoplastin I (a protein, M(r) 5000) and antineoplastin II (an inorganic compound), which when applied to the skin of cancer patients were capable of neutralizing the antibody in vivo through the production of NO in the skin cells due to the stimulation of membrane IANOS of these cells and, subsequently, in erythrocytes in the circulation. RESULTS: Neither antineoplastin I nor antineoplastin II itself enters into the circulation but due to the application of these agents on the skin, the NO synthesis in erythrocytes was normalized in these patients through "feedback" activation and amplification of IANOS activity by NO itself. CONCLUSION: It was found that the resumption of NO synthesis through the neutralization of antibody resulted in favorable modifications of various cancer-associated pathophysiologic consequences. 相似文献
98.
The phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated
kinase (ERK) signaling pathways are important integrators of growth and survival signals originating from extracellular stimuli.
We assessed the importance of these signaling pathways in the growth and survival of 8 breast cell lines (MCF10A, an immortalized
line; and 7 cancer cell lines). The cell lines expressed variable levels of both phosphorylated ERK and phosphorylated Akt,
but these were unchanged by incubation in serum-free medium. Despite continued activity of these pathways, the cells arrested
growth in the absence of serum demonstrating that additional pathways are required for growth. Incubation with the PI3K inhibitor
LY294002 suppressed growth of all cell lines, but most remained viable for at least 7–14 days. This long-term survival may
be attributable to recovery of phospho-Akt by 24–48 h despite the continued presence of active LY294002, suggesting that alternate
pathways may be activating Akt. In contrast, incubation with the MEK inhibitor U0126 not only arrested growth, but also killed
all the cell lines within 2–4 days in the absence of serum; the presence of serum only slighted extended viability, except
in MCF10A and MDA-MB-468 cells, in which serum provided significantly greater protection. It is likely that these signaling
pathways control the level of pro-and anti-apoptotic proteins, yet assessment of Bcl-2 and Bcl-X showed dramatic reduction
in level only when large numbers of cells were dead suggesting this may be a consequence rather than cause of death. Overall,
the results demonstrate that the MEK/ERK pathway represents the more critical pathway for cell survival of these breast cancer
cell lines, and suggest this pathways represents the better target for cancer therapy. 相似文献
99.
100.