Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: a meta-analysis.

Abnormal oxidative stress is an established feature of Alzheimer's disease, but clinical trials aiming to reduce oxidative stress have not yet proven an effective therapy for dementia patients. The purpose of this review is to systematically analyze available data describing markers of oxidative stress and antioxidants in blood from subjects with Alzheimer's disease or those with mild cognitive impairment to highlight potential interactions between peripheral redox changes and central nervous system pathology and contribute to the design of future clinical study. PubMed, SCOPUS and Web of Science were systematically queried to collect studies which have evaluated markers of oxidative stress, levels of antioxidants, copper, transferrin and ceruloplasmin levels in blood from subjects with Alzheimer's disease and matched controls. After application of quality measures, results were aggregated in a random effects analysis. We found that markers of lipid peroxidation are elevated in blood in Alzheimer's disease and in mild cognitive impairment, copper metabolism is dysregulated and total antioxidant capacity is decreased. While surprisingly none of the major antioxidative enzymes are significantly decreased, non-enzymatic antioxidants in blood (particularly uric acid, vitamins A, E and C, α- and ß-carotene) are significantly decreased. There is significant oxidative damage in peripheral blood early in the process of neurodegeneration. We propose that clinical studies assessing cognitive outcomes after antioxidant therapy tailor interventions to individual patients' deficiencies and confirm an improvement in an appropriate serological marker of oxidative stress. This strategy may be most effectively applied in a clinical trial of primary prevention.

Characterizing the mesencephalon using susceptibility-weighted imaging.

BACKGROUND AND PURPOSE: The mesencephalon is involved in a number of human neurodegenerative disorders and has been typically imaged with T1-, T2- and T2*-weighted methods. Our aim was to collect high-contrast susceptibility-weighted imaging (SWI) data to differentiate among and within the basic mesencephalic structures: namely, the red nucleus, substantia nigra, and crus cerebri. MATERIALS AND METHODS: High-resolution SWI, 3D T1-weighted, and T2-weighted data were collected to study contrast in the mesencephalon at 1.5T and 4T. Contrast between structures was calculated for SWI high-pass (HP)-filtered-phase, T1 gradient-echo, and spin-echo T2-weighted data. RESULTS: SWI HP-filtered-phase data revealed similar contrast for the red nucleus and substantia nigra when compared with T2-weighted imaging. However, SWI was able to show structures within the red nucleus, substantia nigra, and medial geniculate body that were invisible on T2-weighted imaging. T1-weighted imaging, on the other hand, did not reveal measurable contrast for any of the structures of interest. SWI HP-filtered-phase data at 4T agreed well with india ink-stained cadaver brain studies, which appear to correlate with capillary density. CONCLUSIONS: With SWI, it is possible to create better anatomic images of the mesencephalon, with improved contrast compared with conventional T1- or T2-weighted sequences.

Spark- and ember-like elementary Ca2+ release events in skinned fibres of adult mammalian skeletal muscle.

1. Using laser scanning confocal microscopy, we show for the first time elementary Ca2+ release events (ECRE) from the sarcoplasmic reticulum in chemically and mechanically skinned fibres from adult mammalian muscle and compare them with ECRE from amphibian skinned fibres. 2. Hundreds of spontaneously occurring events could be measured from individual single skinned mammalian fibres. In addition to spark-like events, we found ember-like events, i.e. long-lasting events of steady amplitude. These two different fundamental release types in mammalian muscle could occur in combination at the same location. 3. The two peaks of the frequency of occurrence for ECRE of mammalian skeletal muscle coincided with the expected locations of the transverse tubular system within the sarcomere, suggesting that ECRE mainly originate at triadic junctions. 4. ECRE in adult mammalian muscle could also be identified at the onset of the global Ca2+ release evoked by membrane depolarisation in mechanically skinned fibres. In addition, the frequency of ECRE was significantly increased by application of 0.5 mM caffeine and reduced by application of 2 mM tetracaine. 5. We conclude that the excitation-contraction coupling process in adult mammalian muscle involves the activation of both spark- and ember-like elementary Ca2+ release events.

Laparoscopic-assisted lumboperitoneal shunt: a simplified technique.

OBJECTIVES: Lumboperitoneal shunt has been advocated as a better alternative to ventriculoperitoneal shunt in communicating hydrocephalus. To minimize the morbidity of subcutaneous tunneling or an open abdominal wound, we developed a simplified technique for laparoscopy-assisted placement of lumboperitoneal shunts. METHODS: Patients deemed candidates for lumboperitoneal shunts underwent laparoscopy-assisted lumboperitoneal shunt placement. Using a Tuohy needle, the neurosurgeon obtains access to the lumbar subthecal space. Simultaneously, the laparoscopist obtains access to the peritoneal cavity with two 5-mm ports for the take down of the descending colon, clearing the way for the passage of the shunt passer from the back into the peritoneal cavity. RESULTS: Over the last 5 years, 45 patients have undergone laparoscopy-assisted lumboperitoneal shunt placement. Patients have been followed with neuropsychiatric examinations, imaging studies, and repeated neurological examinations. No complications related to the laparoscopy have occurred. Neurosurgical complications included postural headaches caused by overdrainage in 4 patients requiring laparoscopic modification of the shunt slit and in 1 patient with acquired Arnold-Chiari I malformation. CONCLUSION: Laparoscopy-assisted lumboperitoneal shunt offers many advantages over percutaneous ventriculoperitoneal or laparoscopic transabdominal lumboperitoneal shunts. The procedure can be performed in less than 30 minutes by any practicing laparoscopist.

Sutureless vascular anastomosis: the VCS clip.

Non-penetrating, arcuate-legged clips facilitate vascular reconstructions and significantly reduce the incidence of anastomotic neointimal hyperplasia. Though originally developed as a microvascular-approximating instrument, by far the largest application has been for hemodialysis vascular access. Long-term studies comparing suture to clip for access creation have demonstrated the clear technical and biological superiority of the clip for this procedure. This "sutureless" vascular anastomotic technique is more demanding than conventional suturing, requiring precise vessel preparation and supervised training.

The utility of the VCS clip for creation of vascular access for hemodialysis: long-term results and intraoperative benefits.

UNLABELLED: The purpose of this study was to compare the effectiveness of the VCS vascular clip approximating system for the creation of hemodialysis access fistulas. 173 new vascular accesses were created, 92 prosthetic grafts and 81 autologous fistulas over a 40-month period. 50 sutured and 42 clipped fistulas comprised the prosthetic graft series, and 33 sutured and 48 clipped cases the autologous series. Risk factors associated with access patency were correlated and the primary patencies compared in the suture versus clipped group. A significant improvement in primary patency was noted for the clipped prosthetic group at all time points studied, with a positive trend also noted for clipped autologous fistulae. CONCLUSIONS: The vascular clipping system (the VCS system) provides both long-term and immediate advantages for vascular access construction. Clips have been used successfully to treat seven consecutive patients with upper extremity arterial steal syndrome without the technical difficulties associated with traditional methods of repair.

An alternative system for cerebrovascular reconstructions: non-penetrating arcuate-legged clips.

Non-penetrating, arcuate-legged titanium clips (VCS) have been utilized successfully over the past five years for a variety of cerebrovascular reconstructions. These applications, including both micro and macrovascular reconstructions, their clinical outcomes and technical considerations are described. Applications include patch angioplasty of cervical carotid endarterectomies, superficial temporal to middle cerebral artery 'bypass' procedures, Takayasu's arteritis and cavernous carotid reconstructions. The non-penetrating clip has proven to be a safe and reliable alternative to suture for these demanding reconstructions. Clips provide the advantages of improved anastomotic compliance, reduced operative time, and reduced incidence of post-operative anastomotic intimal hyperplasia and stenosis. Clip related pitfalls are discussed with recommendations regarding usage.

Impact of nonpenetrating clips on intimal hyperplasia of vascular anastomoses.

Non-penetrating, arcuate-legged titanium clips create an interrupted, non-penetrated, yet compliant vascular anastomoses that is associated with significantly reduced anastomotic neointimal hyperplasia. Recent experimental and clinical studies provide evidence that the non-suture alternative changes the biology of vessel-to-vessel and graft-to-vessel connections that reduces the stimulus for hyperplasia at a number of critical points in the response to injury schema. The compliant, "blood-tight" characteristics of clipped vascular reconstructions are associated with no endothelial injury or intraluminal foreign body, minimal platelet aggregation and laminal flow. Clinical applications including vascular access, femoropopliteal bypass, and closure of carotid endarterectomies are remarkable for the absence of restenosis and preserved anastomotic patency.

A preferred amplitude of calcium sparks in skeletal muscle.

In skeletal and cardiac muscle, calcium release from the sarcoplasmic reticulum, leading to contraction, often results in calcium sparks. Because sparks are recorded by confocal microscopy in line-scanning mode, their measured amplitude depends on their true amplitude and the position of the spark relative to the scanned line. We present a method to derive from measured amplitude histograms the actual distribution of spark amplitudes. The method worked well when tested on simulated distributions of experimental sparks. Applied to massive numbers of sparks imaged in frog skeletal muscle under voltage clamp in reference conditions, the method yielded either a decaying amplitude distribution (6 cells) or one with a central mode (5 cells). Caffeine at 0.5 or 1 mM reversibly enhanced this mode (5 cells) or induced its appearance (4 cells). The occurrence of a mode in the amplitude distribution was highly correlated with the presence of a mode in the distribution of spark rise times or in the joint distribution of rise times and spatial widths. If sparks were produced by individual Markovian release channels evolving reversibly, they should not have a preferred rise time or amplitude. Channel groups, instead, could cooperate allosterically or through their calcium sensitivity, and give rise to a stereotyped amplitude in their collective spark.

Involvement of multiple intracellular release channels in calcium sparks of skeletal muscle.

In many types of muscle, intracellular Ca(2+) release for contraction consists of brief Ca(2+) sparks. Whether these result from the opening of one or many channels in the sarcoplasmic reticulum is not known. Examining massive numbers of sparks from frog skeletal muscle and evaluating their Ca(2+) release current, we provide evidence that they are generated by multiple channels. A mode is demonstrated in the distribution of spark rise times in the presence of the channel activator caffeine. This finding contradicts expectations for single channels evolving reversibly, but not for channels in a group, which collectively could give rise to a stereotyped spark. The release channel agonists imperatoxin A, ryanodine, and bastadin 10 elicit fluorescence events that start with a spark, then decay to steady levels roughly proportional to the unitary conductances of 35%, 50%, and 100% that the agonists, respectively, promote in bilayer experiments. This correspondence indicates that the steady phase is produced by one open channel. Calculated Ca(2+) release current decays 10- to 20-fold from spark to steady phase, which requires that six or more channels be open during the spark.

The spark and its ember: separately gated local components of Ca(2+) release in skeletal muscle.

Amplitude, spatial width, and rise time of Ca(2+) sparks were compared in frog fast-twitch muscle, in three conditions that alter activation of release channels by [Ca(2+)]. A total of approximately 17,000 sparks from 30 cells were evaluated. In cells under voltage clamp, caffeine (0.5 or 1 mM) increased average spark width by 28%, rise time by 18%, and amplitude by 7%. Increases in width were significant even among events of the same rise time. Spontaneous events recorded in permeabilized fibers with low internal [Mg(2+)] (0.4 mM), had width and rise times greater than in reference, and not significantly different than those in caffeine. The spark average in reference rides on a continuous fluorescence "ridge" and is continued by an "ember," a prolongation of width approximately 1 microm and amplitude <0.2, vanishing in approximately 100 ms. Ridge and ember were absent in caffeine and in permeabilized cells. Exposure of voltage-clamped cells to high internal [Mg(2+)] (7 mM) had effects opposite to caffeine, reducing spark width by 26% and amplitude by 27%. In high [Mg(2+)], the ember was visible in individual sparks as a prolongation of variable duration and amplitude up to 1.2. Based on simulations and calculation of Ca(2+) release flux from averaged sparks, the increase in spark width caused by caffeine was interpreted as evidence of an increase in radius of the release source-presumably by recruitment of additional channels. Conversely, spark narrowing suggests loss of contributing channels in high Mg(2+). Therefore, these changes in spark width at constant rise times are evidence of a multichannel origin of sparks. Because ridge and ember were reduced by promoters of Ca(2+)-dependent activation (caffeine, low [Mg(2+)]) and became more visible in the presence of its inhibitors, they are probably manifestations of Ca(2+) release directly operated by voltage sensors.

Spatially segregated control of Ca2+ release in developing skeletal muscle of mice.

1. Confocal laser scanning microscopy was used to monitor Ca2+ signals in primary-cultured myotubes, prepared from forelimbs of wild-type or ryanodine receptor type 3 (RyR3) knockout mice. Myotubes loaded with the acetoxymethyl ester (AM) form of fluo-3 were imaged at rest or under whole-cell patch clamp. 2. Discrete Ca2+ release events were detected in intact wild-type and RyR3-knockout myotubes. They showed almost no difference in amplitude and width, but were substantially different in duration. In wild-type myotubes (660 events, 57 cells) the amplitude was 1.27 (0.85, 1.97) (median (25 %, 75 %)) units of resting fluorescence, the full width at half-magnitude (FWHM) was 1.4 (0.9, 2.3) microm, and the full duration at half-magnitude (FDHM) was 25.3 (9.6, 51.7) ms. In RyR3-knockout myotubes (655 events, 83 cells) the amplitude was 1.30 (0.84, 2.08), FWHM was 1.63 (1.02, 2.66) microm, and FDHM was 43.6 (23.6, 76.9) ms. 3. Depolarization under voltage clamp of both wild-type and RyR3-knockout myotubes produced substantial Ca2+ release devoid of discrete Ca2+ events. Discrete events were still present but occurred without correlation with the applied pulse, largely at locations where the pulse did not elicit release. 4. The local correspondence between voltage control and absence of discrete events implies that the functional interaction with voltage sensors suppresses the mechanism that activates discrete events. Because it applies whether RyR3 is present or not, it is this exclusion by voltage of other control mechanisms, rather than isoform composition, that primarily determines the absence of discrete Ca2+ events in adult mammalian muscle.

Dural closure with nonpenetrating clips prevents meningoneural adhesions: an experimental study in dogs.

OBJECTIVE: Meningospinal and cranial dural adhesions were compared in a canine model, after duraplasty using nonpenetrating clips or penetrating needles and sutures. METHODS: Fourteen dogs underwent bilateral craniotomies and duraplasties, with implantation of dural prostheses (DuraGuard; Biovascular Corp., Minneapolis, MN), using either 6-0 silk sutures or titanium clips (DuraClose; Surgical Dynamics, Norwalk, CT). Fourteen other dogs underwent L3-L4 laminectomies; three longitudinal dural incisions were closed with 6-0 silk sutures, 6-0 polyglactin 910 (Vicryl) sutures, or clips. Groups of eight dogs (four cranially treated and four spinally treated) were killed 6, 12, 24, and 52 weeks after surgery, and specimens were collected for study after perfusion and fixation (two cranial and two spinal dural reconstructions at 52 wk). Evaluations included assessment of the appearance of approximated dural margins and responses to clips, sutures, and dural prostheses (inflammation, foreign body reaction, fibrosis, and severity of meningospinal/meningocerebral adhesions). Data were evaluated using the Wilcoxon signed-rank and McNemar tests. RESULTS: Duraplasties with clips displayed significantly less extensive acute and chronic inflammation, foreign body reaction, and meningoneural adhesions than did repairs with needles and sutures. CONCLUSION: This report is the first long-term experimental study comparing two fundamentally different methods for dural repair in a relevant animal model.

Endoscopic intrauterine surgery in primates: overcoming technical obstacles.

Current protocols for fetal surgery require cesarean section and partial fetal extraction, both of which impart significant risks to the mother and fetus. Endoscopic fetal surgery is less invasive and will likely reduce some of these risks, but the technical difficulties and feasibility in a primate model have yet to be explored fully. Four pregnant baboons (95 days gestation) were anesthetized, their uteruses exposed via an abdominal incision, and blunt-tipped flanged endoscopic ports inserted. Amniotic fluid was removed, and warmed saline was infused to dilate the uterus. To evaluate instrumentation and wound closure, the tip of the snout was externalized and bilateral cleft lip-like defects made. The lips were then endoscopically repaired by suture (Endostitch, U.S. Surgical) or unique nonpenetrating clips (VCS, U.S. Surgical). The saline was then removed, amniotic fluid returned, and the ports carefully removed. After 4 weeks, the fetuses were delivered and evaluated. Eight cleft lip-like defects were successfully repaired in all four cases. Operative time averaged 83 min. No infections, amniotic leaks, or adhesions developed. Survival was 50% with two fetuses delivering within 48 hours postoperatively: one from preterm labor, the other with fetal demise from retroperitoneal hemorrhage after operative blunt abdominal trauma. We demonstrate the feasibility of endoscopic fetal surgery in primates. The use of blunt-tipped flanged ports provides a fluid tight seal and allows appropriate closure of the fetal membranes, but requires laparotomy and uterine exposure. Distension of the uterus with warmed saline affords a larger operating field, enhancing visualization and instrumentation of the fetus. Grasping the fetus through the exposed uterus gives excellent control for repair. However, such control is also needed in a percutaneous approach. Further instrumentation development is needed to accomplish similar control for the percutaneous approach.

Facilitated vascular anastomoses: the one-shot device.

BACKGROUND: A mechanical system for facilitating vascular anastomosis (end-to-side, end-to-end) is described that enables the rapid construction of nonpenetrated, compliant junctions. The instrument (United States Surgical One-Shot system) simultaneously applies either 10 or 12 nonpenetrating, arcuate-legged titanium clips to everted vessel or prosthetic conduit edges. METHODS AND RESULTS: The instrument has been tested in animals (jugular and femoral vein jump grafts in carotid and femoral arteries, interpositional grafts, 20 pigs) and human cadaveric constructs (saphenous veins to left anterior descending coronary arteries, 20 cases, 5 brachiocephalic access fistulas) as end-to-side constructs. Clipped constructs have equivalent or superior physical properties to control sutured constructs (6-0 polypropylene) as gauged by burst and tensile strength. All studies were performed under Food and Drug Administration Good Laboratory Practice standards, and the device has been approved for marketing by the Food and Drug Administration. CONCLUSIONS: The device enables rapid and reproducible vascular anastomotic constructs with vessels as small as 1.8 mm outer diameter. The constructs are flanged, interrupted, and nonpenetrated.

Endoscopic excision and repair of simulated bilateral cleft lips in fetal lambs.

The use of nonpenetrating clips to accomplish wound closure as an alternative to suture in the repair of simulated cleft lips in partially exteriorized fetuses has been described previously. In this study, the fetus is approached endoscopically, and clipped (n = 8) and sutured (n = 4) intrauterine endoscopic repairs in six lambs (90- to 95-day gestation) are compared. Also used was a newly developed harmonic scalpel to create the defects in the fluid environment. Clipped repairs were nearly 10 times faster than sutured repairs (2.7 +/- 0.5 minutes compared with 24 +/- 4 minutes, respectively). Furthermore, suture incited foreign body inflammation, recruited monocytic inflammatory cells, and exhibited notable scarring. The comparison between clipped and sutured repairs extends the previous observations to the realm of endoscopy and reinforces the previous conclusions of this group that the nonpenetrating clip is more rapid and incites less inflammation than suture in fetal wound approximation and repair.

Nonpenetrating clips for coronary anastomosis.

BACKGROUND: A nonsuture clip technique (nonpenetrating titanium clips applied to everted tissue edges at high compressive forces) was used to perform coronary anastomoses in a clinical setting. METHODS: Clipped coronary anastomoses were performed in 10 patients. The anastomoses incorporated the left internal mammary artery to the left anterior descending artery (n = 1) and the saphenous vein to the right coronary artery (n = 5), the posterior descending artery (n = 2), the diagonal artery (n = 2), and one vein-to-vein proximal anastomosis (n = 1). RESULTS: The mean duration for completion of the anastomoses was 15 minutes (range, 7 to 20 minutes). This time was reduced from 20 minutes at the beginning of the clinical experience to 7 minutes for the last 3 patients. No technical complication was related to clip application and all patients had uneventful outcomes. Three anastomoses studied by coronary angiography were patent without stenosis. CONCLUSION: The clipped anastomotic technique has a rapid learning curve, the same safety as suture methods, and the potential for facilitating endoscopic vascular reconstructions.

Neonatal adrenal abscesses.

Unilateral or bilateral suprarenal abscesses are rare in the neonate. We describe 2 cases, an 8-week-old Syrian female with a right, and a 6-week-old white female infant with a left adrenal abscess, both following adrenal hemorrhage. The etiology and treatment are discussed.

A comparative study of apoptosis and cell proliferation in infantile and adult fibrosarcomas.

The infantile fibrosarcoma, a rare tumor phenotypically similar to the adult fibrosarcoma, frequently has a benign course marked by spontaneous regression. Because biologic mechanisms responsible for this regression remain unexplained, an investigation of the role of apoptotic cell death is warranted. The rate of apoptotic cell death has been compared in five cases each of infantile and adult fibrosarcoma by quantitative estimation of in situ DNA double strand breaks. Although positively stained apoptotic cells are evident in all 10 cases, the apoptotic index is significantly higher in infantile cases (mean 6.6% +/- 0.80) compared to adult cases (mean 0.5% +/- 0.08). The proliferative (MIB-1) index of each specimen has been calculated by immunostaining for cell cycle phase-dependent Ki-67 antigen with MIB-1 antibody. Infantile cases have a significantly lower proliferative (MIB-1) index (mean 0.4 +/- 0.15) than adult counterparts (mean 15.9 +/- 3.76). The relatively benign course of the infantile fibrosarcoma may be due to two factors--a significantly lower proliferative (MIB-1) index coupled with enhanced apoptosis.