In vivo nitrate tolerance is not associated with reduced bioconversion of nitroglycerin to nitric oxide

BACKGROUND: In vitro data suggest that reduced bioconversion of nitroglycerin (NTG) to nitric oxide (NO) contributes to the development of vascular and hemodynamic tolerance to NTG. We examined the in vivo validity of this hypothesis by measuring NTG-derived NO formation by in vivo spin-trapping of NO in vascular tissues from nitrate-tolerant and -nontolerant rats. METHODS AND RESULTS: Five groups (n = 6 to 8 each) of conscious chronically catheterized rats received NTG (0.2 or 1 mg/h IV) for 72 hours (nitrate-tolerant groups). Four other groups received either NTG vehicle (placebo, for 72 hours) or were left untreated (control). Nitrate tolerance was substantiated by a reduced (55% to 85%) hypotensive response to NTG in vivo and a reduced relaxation to NTG in isolated aortic rings. NTG-derived NO formation in aorta, vena cava, heart, and liver was measured as NOFe(DETC)2 and NO-heme complexes formed in vivo during 35 minutes combined with ex vivo cryogenic electron spin resonance spectroscopy. NO formation was significantly (P < .05) increased in all tissues in nitrate-tolerant rats in an NTG dose-dependent manner. Furthermore, the amount of NO formed from a bolus dose of NTG (6.5 mg/kg over 20 minutes) was similar in nitrate-tolerant and -nontolerant rats. CONCLUSIONS: The results suggest that vascular and hemodynamic NTG tolerance occurs despite high and similar rates of NO formation by NTG in tolerant and nontolerant target tissues. This finding is compatible with the assumption that reduced biological activity of NO, rather than reduced bioconversion of NTG to NO, contributes to in vivo development of nitrate tolerance.     

The usefulness of three biallelic restriction fragment length polymorphisms versus a polymorphic dinucleotide tandem repeat polymorphism at the low-density-lipoprotein receptor gene locus for diagnosis of familial hypercholesterolemia

The DNA adduct 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been widely used as a biomarker for oxidative stress. Bulky DNA adducts, which are detectable by the 32P-postlabelling method, provide evidence for exposure to and metabolic activation of large, mainly apolar compounds, e.g. polycyclic aromatic hydrocarbons. We determined both types of adducts in placental tissues of 30 term pregnancies and related the adduct levels to the exposure to tobacco smoke and the plasma antioxidant status. Urine and plasma continine concentrations were used to select 10 nonsmokers, 9 nonsmokers exposed to environmental tobacco smoke (ETS) and 11 smoking women. Placental levels of 8-OHdG were 0.84 +/- 0.11, 0.90 +/- 0.21 and 0.83 +/- 0.20/10(5) deoxyguanosine bases (dG) for nonsmokers, nonsmokers exposed to ETS and smokers, respectively. The differences between the groups were not significant. Smoking women had significantly lower plasma vitamin C and beta-carotene concentrations than nonsmoking women or nonsmoking women exposed to environmental tobacco smoke. The 8-OHdG adduct level in placental DNA was inversely correlated with the plasma vitamin E concentration (r = -0.47, P < 0.05). There was no association between placental 8-OHdG adducts and vitamin A, C and beta-carotene in plasma. In total, 15 different adducts could be identified in the 30 placenta samples by the 32P-postlabelling method. There was a strong inter-individual variation in both the number of adducts and adduct intensities. No smoking-related or vitamin-related effects on adduct patterns or intensities were found. Our findings suggests that, within the limits of the methods used, tobacco smoke exposure during pregnancy does not lead to a measurable increase in placental DNA adduct levels and that vitamin E appears to have a protective effect on placental 8-OHdG formation.     

Elastic Low Temperature Anomalies of Solid Hydrogen Crystallites

The property of solid hydrogen (H₂, HD and D₂) not to wet an attractive substrate, can be used to prepare micron sized hydrogen crystals. We used surface acoustic waves (SAW) in the range from 100 MHz to 1 GHz to study the elastic properties of the crystallite-substrate system. The growth of crystallites at temperatures around 3 K can be monitored by the resonant coupling of elastic eigenmodes to the SAW. We observed drastic changes of the resonant coupling for all isotopes when the temperature was varied between 0.15 K and 2.4 K. Possible origins of this unexpecied effect are discussed including a temperature variation of the wetting behavior. For H₂ the impact of the ordering transition of ortho-H₂ was also investigated.     

Implanted functional electrical stimulation hand system in adolescents with spinal injuries: an evaluation

OBJECTIVE: To study the utility and functional benefits of an implanted functional electrical stimulation (FES) system for hand grasp and release in adolescents with tetraplegia secondary to spinal cord injuries. DESIGN: Intervention study with before-after trial measurement with each subject as his or her own control. SETTING: Nonprofit pediatric orthopedic rehabilitation facility specializing in spinal cord injury. PARTICIPANTS: A convenience sample of five adolescents between 16 and 18 years of age with C5 or C6 level tetraplegia at least 1 year after traumatic spinal cord injury. Key muscles for palmar and lateral grasp and release were excitable by electrical stimulation. INTERVENTIONS: A multichannel stimulator/receiver and eight electrodes were surgically implanted to provide stimulated palmar and lateral grasp and release. In conjunction with implantation of the FES hand system, surgical reconstruction in the form of tendon transfers, tendon lengthenings and releases, and joint arthrodeses was performed to augment stimulated hand function. Rehabilitation of the tendon transfers and training in the use of the FES hand system were provided. MAIN OUTCOME MEASURES: Measurements of pinch and grasp force, the Grasp and Release Test (GRT), and an assessment of six activities of daily living (ADL) were administered before implantation of the FES hand system and at regular follow-up intervals. Results of the stimulated response of individual muscles and surgical reconstruction were evaluated using standard and stimulated muscle testing techniques and standard assessment of joint range of motion. All subjects completed followup testing. RESULTS: Lateral and palmar forces were significantly greater than baseline forces (p = .043). Heavy objects on the GRT could only be manipulated with FES, and FES increased the level of independence in 25 of 30 ADL comparisons (5 subjects, 6 activities) as compared to baseline. After training, FES was preferred in 21 of 30 comparisons over the typical means of task completion. Of the 40 electrodes implanted, 37 continue to provide excellent stimulated responses and all of the implanted stimulators have functioned without problems. The surgical reconstruction procedures greatly enhanced FES hand function by either expanding the workspace in which to utilize FES (deltoid to triceps transfer), stabilizing the wrist (brachioradialis to wrist extensor transfer), or stabilizing joints (intrinsic tenodesis transfer, FPL split transfer). CONCLUSION: For five adolescents with tetraplegia, the combination of FES and surgical reconstruction provided active palmar and lateral grasp and release. Laboratory-based assessments demonstrated that the FES system increased pinch force, improved the manipulation of objects, and typically increased independence in six standard ADL as compared to pre-FES hand function. The study also showed that the five adolescents generally preferred FES for most of the ADL tested. Data on the benefits of the implanted FES hand system outside of the laboratory are needed to understand the full potential of FES.     

Comparison of ring block, dorsal penile nerve block, and topical anesthesia for neonatal circumcision: a randomized controlled trial

CONTEXT: Beliefs about the safety and effectiveness of current anesthetics have resulted in many newborns being circumcised without the benefit of anesthesia. OBJECTIVE: To compare ring block, dorsal penile nerve block, a topical eutectic mixture of local anesthetics (EMLA), and topical placebo when used for neonatal circumcision. The placebo represented current practice, with no anesthetic for neonatal circumcision. DESIGN: A randomized controlled trial. SETTING: Antenatal units in 2 tertiary care hospitals in Edmonton, Alberta. PARTICIPANTS: A consecutive sample of 52 healthy, full-term, male newborns, aged 1 to 3 days. INTERVENTIONS: Physiological and behavioral monitoring occurred in a series of trials: baseline, drug application, preparation, circumcision, and postcircumcision. Surgical procedures defined the following 4 stages of the circumcision: cleansing, separation, clamp on, and clamp off. Methemoglobin level was assessed 6 hours after surgery. MAIN OUTCOME MEASURES: Heart rate, cry, and methemoglobin level. RESULTS: Newborns in the untreated placebo group exhibited homogeneous responses that consisted of sustained elevation of heart rate and high-pitched cry throughout the circumcision and following. Two newborns in the placebo group became ill following circumcision (choking and apnea). The 3 treatment groups all had significantly less crying and lower heart rates during and following circumcision compared with the untreated group. The ring block was equally effective through all stages of the circumcision, whereas the dorsal penile nerve block and EMLA were not effective during foreskin separation and incision. Methemoglobin levels were highest in the EMLA group, although no newborn required treatment. CONCLUSIONS: The most effective anesthetic is the ring block; EMLA is the least effective. It is our recommendation that an anesthetic should be administered to newborns prior to undergoing circumcision.     

Pentoxifylline therapy in human immunodeficiency virus-seropositive persons with tuberculosis: a randomized, controlled trial

Macrophage activation and tumor necrosis factor-alpha (TNF-alpha) production are critical in tuberculosis immunity but may result in increased human immunodeficiency virus (HIV) expression and accelerated HIV disease progression in HIV-infected persons. Pentoxifylline inhibits expression of TNF-alpha and HIV. A double-blind, placebo-controlled study of adjunctive therapy with pentoxifylline (1800 mg/day) as a timed-release formulation was done in Ugandan HIV-infected patients with pulmonary tuberculosis. Subjects had early HIV disease (mean CD4 cell count, 380/microL) and did not receive other antiretroviral drugs. Pentoxifylline resulted in decreased plasma HIV RNA and serum beta 2-microglobulin and, in a subset of moderately anemic patients, improved blood hemoglobin levels. Trends were noted toward reduced TNF-alpha production in vitro and improved performance scores, but these did not reach statistical significance. No effect was noted on body mass, CD4 cell count, or survival. Additional studies of more potent TNF-alpha inhibitors in HIV-positive subjects with tuberculosis are warranted.     

Meat tenderness and the calpain proteolytic system in longissimus muscle of young bulls and steers

The objectives of this study were to examine the effects of castration on the calpain proteinase system (mu-calpain, m-calpain, and calpastatin) activities and meat tenderness. Six each, MARC III bulls and steers were slaughtered at approximately 12 mo of age. Longissimus muscle samples were obtained for determining myofibril fragmentation index, Warner-Bratzler shear force, and sensory panel evaluation at 1, 7, and 14 d postmortem, and mu- and m-calpain and calpastatin activities at 24 h postmortem. Bulls produced leaner carcasses with lower (P < .05) quality grades than did steers. Meat from bulls had higher (P < .05) shear force values than meat from steers; however, sensory panelists were unable (P > .05) to detect differences in tenderness or other sensory traits between bulls and steers. Activities of mu- and m-calpain were not affected (P > .05) by castration; however, calpastatin was higher (P < .05) in muscles from the bull carcasses. Lower (P < .05) myofibril fragmentation index values indicate that less proteolysis occurred in muscle from bulls than in muscle from steers during the first 7 d postmortem. Greater calpastatin 24-h activity may be associated with the increased shear force of meat from bulls.