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[A study on histological changes of the intracranial arteries after permanent clipping or ligation.--Part II. Autopsy cases of aneurysmal neck clipping (author's transl)].

Local changes after neck clipping of cerebral aneurysms were studied histopathologically with light microscope in 12 autopsy cases. Seven of them were treated surgically with Yaşargil clips and 5 were treated with Heifetz clips. Another 5 aneurysmal cases, who died without surgery, were studied as the control group. At autopsy, the circle of Willis was fully exposed and meticulously dissected, and the clipped aneurysm was removed en bloc and embedded whole into a paraffin block after the aneurysm clip was removed. The specimen was examined histopathologically in longitudinal serial sections. Time interval between the operation and autopsy ranged from 6 days at the shortest to 11 months at the longest. All cases were congenital berry aneurysms, which showed defects of the tunica media and the internal elastic lamina. The arterial wall between the blades of aneurysm clip showed segmental arterial wall necrosis in 4 (47%) out of 7 cases in the Yaşargil clip group, and in all 5 cases (100%) in the Heifetz clip group. The necrotic change was the strongest at both edges of the blades of the aneurysm clip in the Yaşargil clip group, whereas in the Heifetz clip group the worst changes was found at the mid-convexity of the blades. This is probably due to the different shape and width of the blade of these aneurysm clips. The blade of the Heifetz clip is wider than the blade of the Yaşargil clip, and its convex, almost cylindrical surface is turned toward the vessel, causing a wider ischemic area of the arterial wall with the strongest closing force at the mid-convexity. In the Yaşargil clip group, the degree of arterial wall necrosis was well correlated to the time interval after the clipping. The Heiftz clip group showed arterial wall necrosis even within the 7 days following the operation, and the degree of the necrosis did not show a correlation to the time interval. Definite reactive granulation tissue was not observed until 1 month after the operation, and thereafter the degree of granulation in both groups was proportional to the time interval after the operation. After 3 months following the operation, the blades of the aneurysm clips were covered completely with the granulation tissue and it seemed impossible for the aneurysm clip to slip out at this stage. Up to 14 days after the operation, the aneurysmal lumen was filled with mural, red thrombus and irregular intimal proliferation. After one month following the operation, this was filled with diffuse massive intimal thickening and organized thrombus. After 3 months, intimal thickening filled the aneurysmal lumen almost completely.

Adult↗

Minimizing clip artifacts in multi CT angiography of clipped patients.

PURPOSE: To optimize the multi CTA (MSCTA) protocol, the influence of pitch, kilovoltage peak (kVp), reconstruction algorithm, type, and orientation of the clip on clip-induced artifacts was investigated in a phantom study. Also, the influence of kVp, concentration of contrast material, and clip orientation in clipped patients was studied. METHODS: A phantom containing a clip was scanned with varying parameters. Artifact was quantified with 3D volumetry. Artifact volumes were compared for the different parameters. In addition, the number of artifact streaks was presented as a function of the pitch. Five clipped patients were scanned with 90 kVp and 120 kVp and 5 with 120 kVp and 140 kVp. The artifact area was compared. The visualization at the clip site was evaluated for different clip orientations in 50 patients, and for 140 kVp with 370 mg iodine/mL contrast (I/mL) compared with 120 kVp/300 mg I/mL in 7 patients. RESULTS: Up to a pitch of 0.6, there was hardly an increase in artifact. Higher kVp and linear interpolation resulted in fewer artifacts. Alloy clips containing cobalt produced more artifact than did titanium clips. Clips positioned perpendicular to the scan plane led to significantly less artifact. In patients with clips, scanning with 140 kVp/370 mgI/mL led to a decrease of artifact area and a better visualization of the clip site. The visualization at the clip site was also better for clips perpendicular to the scan plane. CONCLUSIONS: If clip artifacts are to be minimized, we suggest scanning with a pitch of 0.6, by using 140 kVp and 370 mgI/mL contrast.

Artifacts↗

Efficacy of absorbable clips compared with metal clips for cystic duct ligation in laparoscopic cholecystectomy.

PURPOSE: This study was conducted to examine the usefulness and safety of absorbable clips in laparoscopic cholecystectomy (LC). METHODS: We retrospectively compared the clinical data of 328 patients who underwent LC using absorbable clips for cystic duct ligation and 444 patients who underwent LC using metal clips for cystic duct ligation. RESULTS: The mean operative time in the absorbable clip group was significantly shorter than that in the metal clip group. The mean intraoperative blood loss and hospital stay were not significantly different between the two groups. The rate of conversion to open laparotomy in the absorbable clip group was significantly higher than that in the metal clip group, at 6.7% vs 2.3%, respectively. The most common reason for conversion was difficult adhesions and inflammation around the gallbladder. The morbidity of the metal clip group was significantly higher than that of the absorbable clip group, at 8.4% vs 4.0%, respectively. The incidence of major postoperative complications requiring laparotomy did not differ between the two groups. There were no deaths in the absorbable clip group, but 1 of the 444 patients (0.23%) in the metal clip group died from disseminated intravascular coagulation on postoperative day 3. CONCLUSION: The results of this study suggest that absorbable clips are as safe and effective as standard metal clips for vessel and duct ligation in LC.

Adult↗

Histological change in permanently clipped or ligated cerebral arterial wall. Part II: Autopsy cases of aneurysmal neck clipping.

An investigation was carried out on clinical autopsy cases into histological changes in the vessel wall and into the surrounding tissue reaction after permanent clipping. 1. There were 17 autopsy cases of cerebral aneurysm, which included seven cases treated with the Yaşargil clip, five with the Heifetz clip, and five control cases. 2. Clipping period ranged from 6 days to 11 months. Both the Yaşargil and the Heifetz clips, even with long duration of clipping, caused no changes, and inflammatory reaction was slight. 3. As for the necrosis of the vessel wall beneath the blade, the Yaşargil clip produced marked necrosis at the blade edge in 4 of 7 cases (57%), while the Heifetz clip caused necrosis under the midconvexity of the blades in all 5 cases (100%). 4. The granulation tissue reaction round the clip began to occur after one month, and was enough to embed the blade of the clip after three months. We considered it very unlikely for a slip-out accident to occur after this stage. 5. Formation of mural red thrombus and deposition of fibrin with irregular intimal thickening were noted in the aneurysmal lumen in cases clipped for less than 13 days. After one month the intimal thickening was diffuse, and organized thrombus was noted. After three months or more, the aneurysmal lumen was found to have been filled almost completely by intimal thickening. Based on the above finding, the optimum condition for temporary and permanent clips was also considered.

Adult↗

ETA receptor blockade induces fibrosis of the clipped kidney in two-kidney-one-clip renovascular hypertensive rats.

BACKGROUND: In two kidney-one clip renovascular hypertension (2K1C), blood flow is reduced in the clipped kidney leading to ischaemia. The non-clipped kidney is characterized by increased shear stress. Circulating Ang II is elevated. All these factors are stimuli of the paracrine renal endothelin system. Indeed, we demonstrated an activation of the renal endothelin system in the 2K1C rat model. METHODS: We analysed the effects of chronic treatment with the ETA receptor antagonist BQ-123 on blood pressure, heart rate, plasma renin activity, and on the progression of glomerulosclerosis, interstitial fibrosis and vascular remodeling in the clipped and non-clipped kidney. RESULTS: Long-term treatment with BQ-123 led to a fibrotic atrophy of the clipped kidney characterized by a significantly reduced weight of the clipped kidney compared to the clipped kidney of the placebo-treated group. Computer-aided image analysis revealed a markedly enhanced interstitial fibrosis of these clipped kidneys after long-term ETA blockade. The effects of ETA receptor antagonists on the non-clipped kidney were less pronounced. Neither blood pressure nor plasma renin activity were significantly altered by BQ-123 treatment. CONCLUSIONS: The present study indicates that long-term blockade of the activated endothelin system in the clipped kidney of rats with renovascular hypertension using an ETA receptor antagonist led to a fibrotic atrophy of the clipped kidney.

Animals↗

Simulation of the surgical manipulation involved in clipping a basilar artery aneurysm: concepts of virtual clipping. Technical note.

Despite recent advances in three-dimensional imaging based on a voxel-rendering method, these techniques do not simulate the morphological changes that occur during surgery. The authors' goal was to develop a computer-graphics model to simulate the manipulation that occurs during surgery when clipping a cerebral aneurysm. The authors developed an application program to interpolate the contours of models of an artery and an aneurysm clip. The center of displacement was determined inside the arterial model. The directions of displacement were changed to simulate saccular and broad-neck aneurysms, and the intensity of displacement was calculated by using a cosine-based formula. The morphological changes in a saccular aneurysm that may occur during clipping were calculated in x, y, and z coordinates by using sine- and cosine-based formulas. Clip movement was integrated with the aneurysm model, thus simulating the manipulation used during clipping of a cerebral aneurysm. Surgery performed to clip a basilar artery (BA) aneurysm via the transsylvian approach was simulated, in which displacement of the internal carotid artery and clipping of the BA aneurysm were necessary. The movements of an aneurysm clip and clip applicator were designed to represent those occurring when a surgeon actually manipulates a BA aneurysm. The authors have named this methodological tool "virtual clipping." Use of this tool would assist the preoperative choice of clipping style and selection of the best clip.

Basilar Artery↗

Endoscopic clip-marking of lesions using the newly developed HX-3L clip.

Injection of India ink and clipping are relatively well-known methods for marking lesions of the gastrointestinal tract. The use of metal clips provides a radiologically recognizable mark, which is also palpable at surgery. In addition, clips can be extremely useful as landmarks in comparing endoscopic findings with the resected specimen. Previous reports of clip-marking have concentrated on the Olympus (Tokyo, Japan) HX-2L clip, but this clip has the disadvantages of having too wide a diameter to be used through most conventional endoscopes and also a relatively low clip-retention rate, as the depth of its bite is limited. Recently, Olympus has marketed a new clip (HX-3L) designed by the author for hemostasis in cases of gastrointestinal bleeding. This new clip is an improved version of the cassette-type J-clip that was previously reported by the author in this journal. The prime advantage of the HX-3L is that the endoscopist can use it via a panendoscope without any assistance. In addition, it has an excellent bite and a very high level of safety. In terms of function and application, it is completely different from the HX-2L. In addition, the tip (the portion that actually grasps tissue) of the HX-3L is longer and thinner than the HX-2L, thus permitting a firm grasp of the muscularis mucosae layer even when approaching from an upper oblique angle and this, in turn, improves the performance of the clip as a marker.(ABSTRACT TRUNCATED AT 250 WORDS)

Digestive System↗

Use of a new aneurysm clip with an inverted-spring mechanism to facilitate visual control during clip application. Technical note.

When operating on deep-seated cerebral aneurysms, the surgeon's visual control of clip application may be impaired by the clip holder unless adjacent structures are retracted. To improve visual control and reduce the necessity for retraction, the senior author (A.P.) developed a new concept: an aneurysm clip with an inverted-spring mechanism. The clip has two jaws that point away from the clip blades. The jaws of the clip holder articulate with the inner side of the clip jaws. By distending the jaws of the clip holder the blades of the clip are opened and vice versa. Thus the visual field increases while the clip application is proceeding. This instrumentation is useful, especially in cases of deep-seated aneurysms arising from the posterior circulation and in multiple aneurysms. In these latter cases even lesions located contralaterally could be reached with good visual control.

Equipment Design↗

Vascular and cardiac overexpression of endothelin-1 gene in one-kidney, one clip Goldblatt hypertensive rats but only in the late phase of two-kidney one clip Goldblatt hypertension.

OBJECTIVE: To investigate a model of experimental hypertension that exhibits severe hypertrophy of small blood vessels but in which deoxycorticosterone acetate (DOCA) and salt are absent: the one-kidney, one clip model of Goldblatt renovascular hypertension, which is non-renin-dependent, and compare it with the renin-dependent two-kidney, one clip Goldblatt hypertensive rat, in which additionally vascular hypertrophy is less severe. METHODS: Endothelin-1 gene expression in blood vessels and in the heart was examined by Northern blot analysis. RESULTS: After 2 or 4 weeks of application of the silver clip to unilaterally nephrectomized rats, the aorta and mesenteric arteries exhibited a significant increase in the intensity of the 2.3 kb band corresponding to hybridization with endothelin-1 messenger RNA (mRNA) in comparison with results obtained in control unilaterally nephrectomized rats. No increase was noted in the blood vessels of the two-kidney, one clip hypertensive rat at 2 or 4 weeks, but significant increases were found at 8 weeks in aorta, but not in mesenteric arteries. Cardiac abundance of endothelin-1 mRNA was also increased in ventricles and in the left atria of one-kidney, one clip hypertensive rats, but only in the late phase (at 8 weeks) in two-kidney, one clip hypertensive rats. CONCLUSION: Because one-kidney, one clip hypertensive rats presented severe vascular hypertrophy whereas two-kidney, one clip hypertensive rats only did so in the late phase of hypertension, these results lend further support to there being a relationship between vascular hypertrophy and endothelin-1 vascular overexpression in experimental models of hypertension. They also demonstrate that enhancement of the expression of endothelin-1 gene in blood vessels and in the heart of hypertensive rats may occur in the absence of exposure to DOCA and salt, and that endothelin-1 gene overexpression in experimental hypertension occurs early in non-renin-dependent, volume-expanded models such as the one-kidney, one clip or the DOCA-salt hypertensive rat, but only in the progressively non-renin-dependent late phase of the initially renin-dependent volume-contracted two-kidney, one clip hypertensive rat.

Animals↗

Interactions between CLIP-170, tubulin, and microtubules: implications for the mechanism of Clip-170 plus-end tracking behavior.

CLIP-170 belongs to a group of proteins (+TIPs) with the enigmatic ability to dynamically track growing microtubule plus-ends. CLIP-170 regulates microtubule dynamics in vivo and has been implicated in cargo-microtubule interactions in vivo and in vitro. Though plus-end tracking likely has intimate connections to +TIP function, little is known about the mechanism(s) by which this dynamic localization is achieved. Using a combination of biochemistry and live cell imaging, we provide evidence that CLIP-170 tracks microtubule plus-ends by a preassociation, copolymerization, and regulated release mechanism. As part of this analysis, we find that CLIP-170 has a stronger affinity for tubulin dimer than for polymer, and that CLIP-170 can distinguish between GTP- and GDP-like polymer. This work extends the previous analysis of CLIP-170 behavior in vivo and complements the existing fluorescence microscope characterization of CLIP-170 interactions with microtubules in vitro. In particular, these data explain observations that CLIP-170 localizes to newly polymerized microtubules in vitro but cannot track microtubule plus-ends in vitro. These observations have implications for the functions of CLIP-170 in regulating microtubule dynamics.

Animals↗

Endurance of aneurysm clips: mechanical endurance of Yaşargil and Spetzler titanium aneurysm clips.

OBJECTIVE: To determine whether repeated use weakens titanium aneurysm clips, making them unsafe for clinical use. METHODS: Nine Yaşargil (titanium alloy) and five Spetzler (pure titanium) clips were subjected to clinically relevant maneuvers, and the effects on the closing force were assessed. Clips were considered unsafe if 1) the blades crossed, 2) the clips failed to close completely, or 3) the blood pressure could open them. RESULTS: Yaşargil and Spetzler clips significantly (P < 0.01 for both) weakened, by 18.9% and 26.1%, respectively, after 10 minutes of sustained maximal opening. After 100 open-close cycles, Spetzler clips showed no change in closing force, but the closing force of Yaşargil clips decreased significantly (P < 0.01), by a further 12.0%. CONCLUSION: Repeated use weakens Spetzler and Yaşargil clips. All Spetzler and all but one Yaşargil clips were deemed safe for clinical use at the end of the experiments.

Alloys↗

Effects of CLIP (corticotropin-like intermediate lobe peptide) and CLIP fragments on paradoxical sleep in rats.

The effects of the POMC-derived peptide CLIP [corticotropin-like intermediate lobe peptide; ACTH(18-39)] and its shorter fragments ACTH(25-39), ACTH(18-24), and ACTH(20-24) on sleep were investigated in rats housed under normal 12-h light/12-h dark conditions (0600 light on). CLIP (10 ng) or equimolar doses of CLIP fragments, respectively, were injected intracerebroventricularly immediately before the 8-h recording period (0800-1600). It was found that paradoxical sleep (PS) was increased by CLIP (+20%) as well as by the N-terminal CLIP fragment ACTH(18-24) (+18%) and by the pentapeptide ACTH(20-24) (+25%), whereas the C-terminal fragment ACTH(25-39) was ineffective. Slow-wave sleep (SWS) was not influenced. These results clearly demonstrate that CLIP and its N-terminal fragments have selective PS-enhancing effects. CLIP and/or CLIP partial sequences are possible candidates for endogenous PS-inducing peptides involved in the physiological regulation of paradoxical sleep.

Adrenocorticotropic Hormone↗

Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. The Cancer of the Liver Italian Program (CLIP) Investigators.

Prognosis of patients with cirrhosis and hepatocellular carcinoma (HCC) depends on both residual liver function and tumor extension. The CLIP score includes Child-Pugh stage, tumor morphology and extension, serum alfa-fetoprotein (AFP) levels, and portal vein thrombosis. We externally validated the CLIP score and compared its discriminatory ability and predictive power with that of the Okuda staging system in 196 patients with cirrhosis and HCC prospectively enrolled in a randomized trial. No significant associations were found between the CLIP score and the age, sex, and pattern of viral infection. There was a strong correlation between the CLIP score and the Okuda stage. As of June 1999, 150 patients (76.5%) had died. Median survival time was 11 months, overall, and it was 36, 22, 9, 7, and 3 months for CLIP categories 0, 1, 2, 3, and 4 to 6, respectively. In multivariate analysis, the CLIP score had additional explanatory power above that of the Okuda stage. This was true for both patients treated with locoregional therapy or not. A quantitative estimation of 2-year survival predictive power showed that the CLIP score explained 37% of survival variability, compared with 21% explained by Okuda stage. In conclusion, the CLIP score, compared with the Okuda staging system, gives more accurate prognostic information, is statistically more efficient, and has a greater survival predictive power. It could be useful in treatment planning by improving baseline prognostic evaluation of patients with HCC, and could be used in prospective therapeutic trials as a stratification variable, reducing the variability of results owing to patient selection.

Adult↗

Plasma active and acid-activatable renin during the development of one-kidney, one-clip and two-kidney, one-clip hypertension in the rabbit.

Systolic blood pressure in the central ear artery of eight rabbits increased by 21 mmHg (1 mmHg = 133.32 Pa) over 40 days following renal artery clipping and contralateral nephrectomy (one-kidney, one-clip). Plasma active and acid-activatable (pH 2.8) renin did not change significantly. Similar data were obtained from a group of 12 rabbits following renal artery clipping alone (two-kidney, one-clip) except that blood pressure in this group increased for 26 days but then declined until 40 days. Two animals with one-kidney, one-clip hypertension and three rabbits with two-kidney, one-clip hypertension had large increases in plasma active and inactive renin levels, which followed a more exaggerated rise in blood pressure than in the previous two groups. Forty days after unilateral renal artery clipping, the unclipped kidney was removed in 10 animals with two-kidney, one-clip hypertension. A further increase in blood pressure (+29%) occurred in seven of the animals but no change in plasma active or inactive renin. Results were compared with two groups of control animals, a unilateral nephrectomy group and a laparotomy group. None of the surgical procedures used produced a consistent pattern of change in the relative amounts of active and inactive renin in plasma. No marked changes in sodium, potassium, or water balance occurred in any group of animals.

Animals↗

Two-kidney, one clip and one-kidney, one clip hypertension in mice.

The mouse remains the animal of choice in transgenic experiments, creating a need for methods of evaluating the physiology of genetically modified animals. We have established and characterized two murine models of renovascular hypertension known as the two-kidney, one clip and one-kidney, one clip models. The appropriate size of the clip lumen needed to induce high blood pressure was determined to be 0.12 mm. Clips with a lumen of 0.11 mm induced a high percentage of renal infarction, and clips with a 0.13-mm opening did not produce hypertension. Four weeks after clipping, two-kidney, one clip hypertensive mice exhibited blood pressure approximately 20 mm Hg higher than their sham-operated controls. After a similar period, this increase reached almost 35 mm Hg in the one-kidney, one clip model. Depending on the model, mice develop either renin-dependent or renin-independent hypertension. Both models are characterized by the development of cardiovascular hypertrophy.

Animals↗

[Laparoscopically placed clips on the human cystic duct--an experimental comparison of dislocation between resorbable and titanium clips].

Kryopreserved specimens of cystic ducts were used for displacement tests to investigate the security of different laparoscopic clips. The cystic duct was fixed, and the transverse placed clips were distracted in axial direction and the forces registered. The median values of the six investigated clips ranged between 4.1 N and 11.2 N with a highly significant difference (P < 0.001, Kruskal-Wallis ANOVA). In detail, both resorbable clips (polydioxanone, polyglyconate/polyglycol acetate) were superior to the four titanium clips (P < 0.005, Wilcoxon test). In addition to the advantage of complete biodegradibility, these data favour the use of absorbable clips because holding force is better than that of titanium clips.

Biodegradation, Environmental↗

Differential regulation of osteopontin expression in the clipped and nonclipped kidney of two-kidney, one-clip hypertensive rats.

BACKGROUND: Osteopontin (Opn) is highly upregulated in many different animal models of renal disease, where it is suspected to participate in progression of the disease. In some models, angiotensin II (Ang II) seems to induce the elevated Opn production. Therefore, we examined the regulation of Opn in two-kidney, one-clip (2K1C) hypertensive rats, in which Ang II mediates the elevated blood pressure. METHODS: At days 7, 14, and 28, the clipped and nonclipped kidneys of hypertensive or sham-operated rats were analyzed for osteopontin protein, mRNA expression and mononuclear cell infiltration by imumunohistochemistry, in situ hybridization, and Northern blot analysis. Rats were treated with the Ang II type 1 receptor antagonist Valsartan starting 14 days after clipping. RESULTS: In sham-operated rats, Opn was mainly localized to cells of the thin ascending limbs of the outer medulla. No significant Opn staining was observed in cortical tubules. Focally defined tubular cortical Opn staining was observed in clipped and contralateral kidneys of hypertensive animals at days 14 and 28. Osteopontin protein expression correlated with the mRNA expression detected by in situ hybridization and Northern blot. Treatment with Valsartan reduced osteopontin staining by 51%, mRNA by 47%, and mononuclear cell number by 97% in nonclipped kidneys compared to untreated two-kidney, one-clip animals. In clipped kidneys, however, Opn protein and mRNA expression was not reduced, but a 240% increase in interstitial mononuclear cell number was observed. CONCLUSIONS: Osteopontin is involved in the induction of nephrosclerosis in renovascular hypertension, probably by a mechanism augmenting monocyte infiltration. Angiotensin II appears to be an important inducer of Opn in the nonclipped kidney. Ischemic conditions may regulate Opn expression in the clipped kidney.

Angiotensin Receptor Antagonists↗

Development and characterization of a novel, graded model of clip compressive spinal cord injury in the mouse: Part 1. Clip design, behavioral outcomes, and histopathology.

In order to take advantage of various genetically manipulated mice available to study the pathophysiology of spinal cord injury (SCI), we adapted an extradural clip compression injury model to the mouse (FEJOTA mouse clip). The dimensions of the modified aneurysm clip blades were customized for application to the mouse spinal cord. Three clips with different springs were made to produce differing magnitudes of closing force (3, 8, and 24 g). The clips were calibrated regularly to ensure that the closing force remained constant. The surgical procedure involved a laminectomy at T3 and T4, followed by extradural application of the clip at this level for 1 min to produce SCI. Three injury severities (3, 8, and 24 g), sham (passage of dissector extradurally at T3-4), and transection control groups were examined (n = 12/group). Quantitative behavioural assessments using the Basso, Beattie, and Bresnahan (BBB; H > 46; df = 4; p < 0.001; Kruskal-Wallis one-way ANOVA) and inclined plane (IP; F = 123; df = 4; p < 0.0001; two-way repeated measures ANOVA) tests showed a significant graded increase in neurological deficits with increasing severity of injury. By day 14, the motor recovery of the mice plateaued. Qualitative examination of the injury site morphology indicated that microcystic cavitation, degenerating axons, and robust astrogliosis were characteristic of the murine response to clip compressive SCI. Morphometric analyses of H&E/Luxol Fast Blue stained sections at every 50 microm from the injury epicenter indicated that with greater injury severity there was a progressive decrease in residual tissue (F = 220, df = 3; p < 0.0001; two-way ANOVA). In addition, statistically significant differences were found in the amount of residual tissue at the injury epicenter between all of the injury severities (p < 0.05, SNK test). This novel, graded compressive model of SCI will facilitate future studies of the pathological mechanisms of SCI using transgenic and knockout murine systems.

Animals↗