Increased seizure threshold in mice lacking aquaporin-4 water channels

Mice deficient in the glial water channel aquaporin-4 (AQP4) show decreased cerebral edema and improved neurological outcome following water intoxication or ischemic challenge. In this report, we tested seizure susceptibility in AQP4 mice. AQP4 mice and wild-type controls were given the chemoconvulsant pentylenetetrazol (PTZ) and monitored for seizure activity. At 40 mg/kg PTZ, all wild-type mice exhibited seizure activity, whereas six of seven AQP4 mice did not exhibit seizure activity. At 50 mg/kg PTZ, both groups exhibited seizure activity; however, the latency to generalized (tonic-clonic) seizures was significantly lower in wild-type than AQP4 mice. These results suggest that glial water channels may modulate brain excitability and the initiation and generalization of seizure activity.     

Relationship between advanced glycoxidation end products,inflammatory markers/acute-phase reactants,and some autoantibodies in chronic hemodialysis patients

Uremia and dialysis treatment are associated with uncorrected oxidative and carbonyl stress and microinflammation. Elevation of both oxidative/carbonyl stress end products (advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), and advanced lipoperoxidation end products (ALEs), autoantibodies against modified biological structures, and acute-phase reactants (e.g., C-reactive protein [CRP], fibrinogen) seems to take part in the development of various complications, among them accelerated atherosclerosis. These pathogenic mechanisms are supposed to act synergically; nevertheless, oxidative stress shows a closer relationship to inflammation and acute-phase reaction than advanced glycation. Its end product, AOPP, could, thus, represent a biochemical marker of specific importance.     

The initial experience with the ATS Medical mechanical cardiac valve prosthesis

BACKGROUND: From May 1994 through October 2000, a total of 1,146 patients underwent valve replacement with the ATS Medical mechanical cardiac valve prosthesis under a study protocol approved by international ethics committees (non-United States participants) or under a United States Food and Drug Administration-approved Investigational Device Exemption study. The study took place at 19 domestic and three international centers. METHODS: As required by the Food and Drug Administration's Heart Valve Guidance Document, only isolated implants were included in the study (double-valve implants were excluded), with operative and follow-up data collected from each center. RESULTS: Aortic valve replacement (AVR) was conducted in 801 patients (309 with coronary bypass) and mitral valve replacement (MVR) in 345 patients (78 with coronary bypass). Overall operative (< or = 30 days post implant) mortality was 2.1% (17 AVR = 2.1%, 7 MVR = 2.0%), 7 of which (AVR = 4, MVR = 3) were valve related. In 2,086 patient-years (1,459 AVR patient-years, 627 MVR patient-years) of follow-up, there were an additional 50 patient deaths of these, 18 were valve related, 9 due to anticoagulant related bleeding, 5 sudden/unexplained, and 1 each after stroke, thrombosis, prosthetic valve endocarditis, and thromboembolism. Late (>30 days post implant) valve-related complications included: transient and chronic thromboembolism (27 AVR (linearized rate 1.85%/patient-year) and 20 MVR (3.19%/patient-year), of which 11/47 (0.53%/patient-year) had chronic deficits, thrombosis (1 AVR = 0.07%/patient-year and 4 MVR = 0.64%/patient-year), paravalvular leak (10 AVR = 0.69%/patient-year and 8 MVR = 1.28%/patient-year), anticoagulant related hemorrhage (34 AVR = 2.33%/patient-year and 8 MVR = 1.28%/patient-year), prosthetic valve endocarditis (3 AVR = 0.21%/patient-year and 2 MVR = 0.32%/patient-year), and structural valve failure or dysfunction (0%). Echocardiographic gradients were proportional to valve size and did not significantly change over the follow-up period. CONCLUSIONS: This study documented the ATS Medical mechanical cardiac valve prosthesis to be a valuable addition to the surgeon's armamentarium in the treatment of cardiac valvular disease.     

Spouses and unrelated friends of probands as controls for stroke genetics studies

To plan a multisite, ischemic stroke genetic study, stroke patients were surveyed about the availability and characteristics of a convenience sample of spouse/friend controls. 65% of all stroke-affected probands reported a living spouse. A more detailed survey was conducted at the University of Virginia, Charlottesville, Va., USA: 51% of stroke patients reported a living, stroke-free spouse who would be willing to serve as a control, and 49% reported having a stroke-free friend who would be willing to serve as a control. Overall, 75% of stroke patients reported at least 1 individual willing to participate as a control. Cases without an identified control were more likely to be non-white (48%) than were cases with a control (13%; p = 0.00004). Cases were older than controls (67.3 vs. 59.2 years; p = 0.000002), and a greater proportion of cases than controls were male (57 vs. 33%; p = 0.0002). Without proper attention to matching, the use of a spouse/friend convenience sample would result in imbalances in basic demographic characteristics.     

The effects of autologous platelet gel on wound healing

Laser resurfacing techniques have become a popular means of achieving rejuvenation of damaged skin. Interest is great in attempting to speed re-epithelialization and healing so that patients can return to their normal activities as quickly as possible. Previous studies have demonstrated that wounds heal more quickly when they are covered and kept moist than when they are left open to the air. Until now, no study has been conducted to investigate whether the healing process of a superficial skin burn might be accelerated by the use of an autologous platelet gel as a biologic dressing. Our study of five pigs showed that autologous platelet gel can influence wound healing by stimulating an intense inflammatory process that leads to highly significant increases in the production of extracellular matrices and granulation tissue. The platelet gel accelerated vascular ingrowth, increased fibroblastic proliferation, and accelerated collagen production. However, the gel did not appear to accelerate re-epithelialization. The aggressive production of granulation tissue and the acceleration of collagen production might mean that autologous platelet gel will have a future role in the treatment of burns because the highly vascularized bed it helps create should promote the success of skin grafting in patients with deep partial-thickness and full-thickness burns.     

Comparison of functional and quality-of-life outcomes in patients with and without palatomaxillary reconstruction: a preliminary report

BACKGROUND: Orodental rehabilitation of hemipalatomaxillectomy defects can be accomplished by using a prosthetic obturator or a vascularized bone-containing free flap. Whereas prosthetic obturation offers several advantages, including the opportunity for immediate dental restoration without the need for further surgery, vascularized bone grafts provide permanent closure of the oronasal communication and bone sufficient for the placement of osseointegrated implants. OBJECTIVE: To compare the functional and quality-of-life (QOL) outcomes in patients rehabilitated with a prosthetic obturator with defect-matched patients who underwent reconstruction with a vascularized bone-containing free flap. METHODS: Four hemipalatomaxillectomy patients rehabilitated with a tissue-borne prosthetic obturator were compared with 4 defect-matched hemipalatomaxillectomy patients who underwent reconstruction with a vascularized bone-containing free flap. All of the patients were objectively assessed for speech, mastication, and QOL. Functional status was assessed by mastication testing, voice analysis, and nasorhinometry. Swallowing-related QOL was assessed using a patient-reported, validated swallowing QOL questionnaire, and donor site morbidity was assessed using upper extremity and lower extremity questionnaires. RESULTS: Patients who underwent reconstruction with a vascularized bone-containing free flap achieved higher mastication and speech assessment scores with less oronasal reflux than defect-matched patients rehabilitated with a prosthetic obturator. Swallowing QOL and donor site assessments demonstrated that compared with their prosthetic counterparts, reconstruction patients enjoyed a better QOL without incurring significant donor site morbidity. CONCLUSIONS: Although palatomaxillary reconstruction with vascularized bone-containing free flaps requires a second operative site, this method of orodental rehabilitation of the hemipalatomaxillectomy defect can achieve superior functional and QOL outcomes relative to defect-matched patients rehabilitated with a prosthetic obturator.     

Effects of Doxorubicin (Adriamycin) and [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (ICRF-187) on skeletal muscle protease activities

Adverse effects of doxorubicin (adriamycin) have been reported to be due to iron-catalyzed free radical formation, which can be prevented with the cytoprotective chelating agent [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (dexrazoxane; ICRF-187). Affected tissues include the heart, gastrointestinal tract, and kidney. However, there is very little information on the effects of adriamycin on skeletal muscle, despite the fact that there is direct and indirect evidence to show that both adriamycin and ICRF-187 are myotoxic. To investigate the mechanisms of cytotoxicity of these agents in skeletal muscle, we have conducted a systematic investigation of the activities of the major lysosomal (dipeptidyl aminopeptidase I and II and cathepsins B, D, H, and L) and cytoplasmic (alanyl-, arginyl-, and leucyl aminopeptidase, dipeptidyl aminopeptidase IV, tripeptidyl aminopeptidase, and proline endopeptidase) muscle proteases. These enzymes play an important role in normal cellular function and represent potential targets for toxic and protective agents. Male Wistar rats (approx. 0.2 kg) were subjected to a pretreatment phase of 30 min followed by a treatment stage of either 2.5 or 24 h. The pretreatment involved injection of a single bolus of either saline (0.15 mol/l NaCl; 5 ml/kg ip) or ICRF-187 (100 mg/kg; 5 ml/kg ip). After 30 min, rats were injected again with a single bolus of either adriamycin (5 mg/kg; 10 ml/kg ip) or saline (0.15 mol/l NaCl; 10 ml/kg ip) in the treatment phase. At either 2.5 or 24 h after the last adriamycin or saline injection, rats were killed for subsequent dissection of the gastrocnemius muscle for analysis. In the 2.5-h study, there were significant reductions in cathepsin D activities of adriamycin-treated rats compared to saline injected control (p = 0.02). In both 2.5- and 24-h studies there were also significant differences (p = 0.05) in cathepsin H activities between rats treated with adriamycin and ICRF-187, although these differences were not significant when data were compared with corresponding saline-injected rats. There were no other overt effects for any of the other proteases at either 2.5 or 24 h. We conclude that both adriamycin and ICRF-187 have very little effect on the activities of muscle proteases and that altered proteolysis is not involved in the reported pathological reactions induced by these agents.     

A synthetic glycine-extended bombesin analogue interacts with the GRP/bombesin receptor

alpha-amidation of a peptide (which takes place from a glycine-extended precursor) is required to produce biologically active amidated hormones, such as gastrin-releasing peptide (GRP)/Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH(2) (bombesin). It was shown that glycine-extended gastrin mediates mitogenic effects on various cell lines by interacting with a specific receptor, different from the classical CCK(1) or CCK(2) receptors. On the basis of this observation, we have extended the concept of obtaining active glycine-extended forms of others amidated peptides to produce new active analogues. In this study, we have tested the biological behaviour of a synthetic analogue of the glycine-extended bombesin (para-hydroxy-phenyl-propionyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-Gly-OH or JMV-1458) on various in vitro models. We showed that compound JMV-1458 was able to inhibit specific (3-[125I]iodotyrosyl(15)) GRP ([125I]GRP) binding in rat pancreatic acini and in Swiss 3T3 cells with K(i) values of approximately 10(-8) M. In isolated rat pancreatic acini, we found that JMV-1458 induced inositol phosphates production and amylase secretion in a dose-dependent manner. In Swiss 3T3 cells, the glycine-extended bombesin analogue dose-dependently produced [3H]thymidine incorporation. By using potent GRP/bombesin receptor antagonists, we showed that this synthetic glycine-extended bombesin analogue induces its biological activities via the classical GRP/bombesin receptor.