Human neural stem cells genetically modified to express human nerve growth factor (NGF) gene restore cognition in the mouse with ibotenic acid-induced cognitive dysfunction.

Alzheimer's disease (AD) is characterized by degeneration and loss of neurons and synapses throughout the brain, causing the progressive decline in cognitive function leading to dementia. No effective treatment is currently available. Nerve growth factor (NGF) therapy has been proposed as a potential treatment of preventing degeneration of basal forebrain cholinergic neurons in AD. In a previous study, AD patient's own fibroblasts genetically modified to produce NGF were transplanted directly into the brain and protected cholinergic neurons from degeneration and improved cognitive function in AD patients. In the present study, human neural stem cells (NSCs) are used in place of fibroblasts to deliver NGF in ibotenic acid-induced learning-deficit rats. Intrahippocampal injection of ibotenic acid caused severe neuronal loss, resulting in learning and memory deficit. NGF protein released by F3.NGF human NSCs in culture medium is 10-fold over the control F3 naive NSCs at 1.2 µg/10(6) cells/day. Overexpression of NGF in F3.NGF cells induced improved survival of NSCs from cytotoxic agents H2O2, Aß, or ibotenic acid in vitro. Intrahippocampal transplantation of F3.NGF cells was found to express NGF and fully improved the learning and memory function of ibotenic acid-challenged animals. Transplanted F3.NGF cells were found all over the brain and differentiated into neurons and astrocytes. The present study demonstrates that human NSCs overexpressing NGF improve cognitive function of learning-deficit model mice.

Runoff losses of suspended sediment, nitrogen, and phosphorus from a small watershed in Korea.

Nutrients and sediments in runoff lead to the degradation of water quality of lakes and streams. The development of schemes to mitigate such degradation requires a characterization of the underlying transport processes. The objectives of this study were to develop annual and seasonal load-discharge relationships for suspended sediment (SS), total nitrogen (TN), and total phosphorus (TP) losses from a small mixed land use watershed and to use these relationships to explicate the annual and monthly patterns of losses of these species. Data from 1996 to 2004 were used to develop load-discharge relationships for SS, TN, and TP at the HP#6 watershed, a subwatershed of the Balhan reservoir watershed located in Bongdam-myun and Paltan-myun, Gyeonggi-do, Korea. Standard least squares curve fitting and S-estimation procedures were used to fit power functions to the data collected over this time period. The fitted load-discharge relationships are indicative of seasonal variations in SS and TN and of TP losses from HP#6. The exponents of the fitted power functions for TN and TP in the fall, for TP in summer season, and for SS in all seasons are >1, indicating that the concentrations of these species increase as flow rate increases. Most of the SS, TN, and TP transported in runoff left the watershed between April and September; thus, cost-efficient strategies can be established by focusing on this period. Further study of the seasonal variations is required for a better characterization of seasonal losses of SS, TN, and TP in runoff from the HP#6 watershed.

Mechanisms of recurrent functional mitral regurgitation after mitral valve repair in nonischemic dilated cardiomyopathy: importance of distal anterior leaflet tethering.

BACKGROUND: Recurrent functional mitral regurgitation (MR) has been reported after mitral valve repair with annuloplasty in patients with dilated cardiomyopathy, but the mechanism is not understood completely. The authors sought to identify abnormalities of the mitral valve and left ventricle that are associated with recurrent MR after mitral annuloplasty. METHOD AND RESULTS: In 104 patients with idiopathic dilated cardiomyopathy who underwent annuloplasty for functional MR, basal mitral anterior leaflet angle, distal mitral anterior leaflet angle (ALAtip), posterior leaflet angle, coaptation depth, tenting area, mitral annular dimensions, left ventricular volumes, and MR severity were quantified by echocardiography before surgery and at 6-month intervals after it. Compared with patients without MR recurrence (n=79), patients with recurrent MR (defined as > or =2+) (n=25) had greater ALAtip (P<0.001) and basal mitral anterior leaflet angle (P<0.001), greater coaptation depth and tenting area (P<0.001), larger left ventricular volumes (P<0.001), and worse left ventricular ejection fraction (P<0.05) but similar mitral annular dimensions and postoperative exaggeration in posterior leaflet angle. Multivariable analysis identified postoperative ALAtip as the major determinant of postoperative MR. Receiver operator characteristic curves identified preoperative ALAtip as the best predictor of MR recurrence (area under curve, 0.98). For ALA(tip) >25 degrees, the sensitivity, specificity, and positive and negative predictive values in predicting recurrent MR were 88%, 94%, 82%, and 93%, respectively. Three distinct patterns of anterior leaflet tethering (minimal, basal, and distal) with an increasing risk of recurrent MR were identified. CONCLUSIONS: Posterior leaflet tethering is invariable after mitral annuloplasty, rendering postoperative mitral competence highly dependent on distal anterior leaflet mobility.

Antihyperalgesic effects of vanilloid-1 and bradykinin-1 receptor antagonists following spinal cord injury in rats.

OBJECT: The authors previously discovered that genes for the bradykinin-1 (B1) receptor and the transient receptor potential vanilloid subtype 1 (TRPV1) were overexpressed in animals exhibiting thermal hyperalgesia (TH) following spinal cord injury (SCI). They now report the effect of TRPV1 (AMG9810) and B1 (Lys-[Des-Arg9,Leu8]-bradykinin) antagonists on TH in animals following SCI. METHODS: The rats were subjected to contusion SCI and then divided into groups in which TH did or did not develop. The animals from both groups were given either AMG9810, Lys-(Des-Arg9,Leu8)-bradykinin, or the drug-specific vehicle (control groups). Animals were tested for TH preinjury and at regular intervals after SCI by using the hindlimb withdrawal latency test. CONCLUSIONS: The administration of AMG9810 likely improves TH as a result of a generalized analgesic effect, whereas the effect of Lys-(Des-Arg9,Leu8)-bradykinin appears more specific to the reversal of TH. This information has potential usefulness in the development of treatment strategies for post-SCI neuropathic pain.

Targeting of amacrine cell neurites to appropriate synaptic laminae in the developing zebrafish retina.

Cellular mechanisms underlying the precision by which neurons target their synaptic partners have largely been determined based on the study of projection neurons. By contrast, little is known about how interneurons establish their local connections in vivo. Here, we investigated how developing amacrine interneurons selectively innervate the appropriate region of the synaptic neuropil in the inner retina, the inner plexiform layer (IPL). Increases (ON) and decreases (OFF) in light intensity are processed by circuits that are structurally confined to separate ON and OFF synaptic sublaminae within the IPL. Using transgenic zebrafish in which the majority of amacrine cells express fluorescent protein, we determined that the earliest amacrine-derived neuritic plexus formed between two cell populations whose somata, at maturity, resided on opposite sides of this plexus. When we followed the behavior of individual amacrine cells over time, we discovered that they exhibited distinct patterns of structural dynamics at different stages of development. During cellular migration, amacrine cells exhibited an exuberant outgrowth of neurites that was undirected. Upon reaching the forming IPL, neurites extending towards the ganglion cell layer were relatively more stable. Importantly, when an arbor first formed, it preferentially ramified in either the inner or outer IPL corresponding to the future ON and OFF sublaminae, and maintained this stratification pattern. The specificity by which ON and OFF amacrine interneurons innervate their respective sublaminae in the IPL contrasts with that observed for projection neurons in the retina and elsewhere in the central nervous system.

Left atrial volume: a powerful predictor of survival after acute myocardial infarction.

BACKGROUND: After acute myocardial infarction (AMI), diastolic function assessed by Doppler echocardiography provides important prognostic information that is incremental to systolic function. However, Doppler variables are affected by multiple factors and may change rapidly. In contrast, left atrial (LA) volume is less influenced by acute changes and reflects subacute or chronic diastolic function. This may be of importance when one assesses risk in patients with AMI. METHODS AND RESULTS: Three hundred fourteen patients with AMI who had a transthoracic echocardiogram with assessment of left ventricular (LV) systolic and diastolic function and measurement of LA volume during admission were identified. The LA volume was corrected for body surface area, and the population was divided according to LA volume index of 32 mL/m2 (2 SDs above normal). LA volume index was >32 mL/m2 in 142 (45%). The primary study end point was all-cause mortality. During follow-up of 15 (range 0 to 33) months, 46 patients (15%) died. LA volume index was a powerful predictor of mortality and remained an independent predictor (hazard ratio 1.05 per 1-mL/m2 change, 95% CI 1.03 to 1.06, P<0.001) after adjustment for clinical factors, LV systolic function, and Doppler-derived parameters of diastolic function. CONCLUSIONS: Increased LA volume index is a powerful predictor of mortality after AMI and provides prognostic information incremental to clinical data and conventional measures of LV systolic and diastolic function.