Cholera and pertussis toxins each contain a subunit with ADP-ribosyltransferase activity, sharing a region of nearly identical amino acid sequence near the NH2 terminus. Previous investigations have shown that substitution of a lysine residue for Arg-9 in the catalytic A subunit of pertussis toxin substantially eliminates its enzyme activity. We now report that substitution of lysine for the position-equivalent Arg-7 of cholera toxin subunit A leads to a similar loss of catalytic activity. This result suggests a correlation of function with structure between the sequence-related cholera and pertussis toxin A subunits and may contribute to the design of a vaccine containing an enzymatically inert analog of cholera toxin. 相似文献
Background: Electrical stimulation (ES) of the stomach has been shown to modulate LESP. Electrical stimulation, using neural high frequency stimulation (NGES) can induce contractions of the smooth muscle of the gut. The purpose of this study was to determine if electrical stimulation of the LES can affect LESP. Methods: Four female hound dogs, weight: 20–25 kg, underwent an esophagostomy that allowed the introduction of a sleeve manometry catheter into the esophagus. They were also implanted with a pair of electrodes along the longitudinal axis of the LES. After 3 weeks of recovery, they underwent esophageal manometry recording during control and ES, performed randomly on separate days, using 4 different stimulations: 1‐Low frequency: freq: 6 cycles/min, pulse: 350 milisec, amp: 5 mAmp; 2 High‐frequency: freq: 50 Hz, pulse: 1 milisec, amp: 5 mAmp; 3‐ NGES: freq: 50 Hz, pulse:20 milisec, amp:10 volts; 4‐ High‐frequency, circular: freq: 20 Hz, pulse:1 milisec, amp:5 mAmp. All recordings were performed 1 hour after consumption of 3 ounces of canned dog food, to prevent fluctuations in LESP and under mild sedation (acepromazine 0.5 mg kg1). Tests consisted, during ES days, of 3 periods of 20 minutes each: control , stimulation and post stimulation. The effect of NGES was also tested under anesthesia and following administration of L‐NAME 50 mg kg1 IV. and also atropine 0.05 mg kg1 IV. Analysis: area under the curve (AUC) and pressure were compared among the 3 periods. Data shown as mean ± SD, ANOVA and t‐test, p < 0.05. Results: Sustained increase in LESP was observed during low frequency stimulation, 32.1 ± 12.8 vs. 42.4 ± 18.0 vs. 50.1 ± 23.6, control vs. stimulation vs. post stimulation respectively, p = 0.013. AUC also significantly increased during and after stimulation, 39,320.3 ± 15,722 vs. 51,294 ± 21,826 vs. 59,823.6 ± 28,198.4 mmHgxsec, control vs. stimulation vs. post stimulation respectively, p = 0.01. There was no significant change with other types of ES. NGES induced an initial rise in LESP followed within few seconds by relaxation with slow resumption of pressure over a 1 minute period. L‐NAME increased LESP and augmented the initial rise in LESP following NGES but markedly diminished or abolished the relaxation phase. Atropine lowered LESP and abolished the initial rise in LESP induced by NGES. Conclusions: Low frequency ES of the LES increases LESP in conscious dogs. NGES has dual effect on LESP: an initial stimulation, cholinergically mediated, followed by relaxation mediated by nitric oxide. 相似文献
We investigate whether symptoms of pressure, tightness, and/or pain in the chest, neck, and/or throat after administration of the 5HT1B/1D agonist avitriptan were associated with objective impairment of the myocardial function on 12-lead electrocardiogram (ECG), continuous ECG (Holter) monitoring, and echocardiography. Migraine sufferers who in two-thirds of alt attacks treated with sumatriptan had experienced chest/throat/neck symptoms were chosen for study. Baseline measures included vital signs, a 12-lead ECG and an echocardiogram. Patients ( n =51) who had no clinically significant abnormality at baseline received a high dose (150 mg) of avitriptan orally outside of a migraine attack. If pressure, tightness, and/or pain in the chest, neck, and/or throat occurred, an ECG was obtained, and a repeat echocardiogram was done while the symptoms were present in order to monitor for impairment of myocardial function. If symptoms of these types did not occur within 60 min after administration of the study drug, a second echocardiogram was obtained. Forty-five patients (88%) reported at least one adverse event and 23 (45%) experienced pressure, tightness, and/or pain in the chest, neck, and/or throat after administration of avitriptan. No clinically significant myocardial abnormalities were observed in any patient, even in those who had experienced the targeted symptoms. No other serious adverse event occurred. We concluded that the typical 5HT1B/1D agonist-induced chest/throat/neck symptoms are most unlikely to be of cardiovascular origin. 相似文献
The use of spirometry for early detection of chronic obstructive pulmonary disease (COPD) is still an issue of debate, particularly
because of a lack of convincing evidence that spirometry has an added positive effect on smoking cessation. We hypothesise
that early detection of COPD and confrontation with spirometry for smoking cessation may be effective when applying an approach
we have termed "confrontational counselling"; a patient-centred approach which involves specific communication skills and
elements of cognitive therapy. An important aspect is to confront the smoker with his/her airflow limitation during the counselling
sessions. The primary objective of this study is to test the efficacy of confrontational counselling in comparison to regular
health education and promotion for smoking cessation delivered by specialized respiratory nurses in current smokers with previously
undiagnosed mild to moderate airflow limitation. 相似文献
Kaposi's sarcoma-associated herpesvirus (KSHV) infection is a prerequisite for the development of Kaposi's sarcoma (KS). Blocking lytic KSHV replication may hinder KS tumorigenesis. Here, we report potent in vitro anti-KSHV activity of 2'-exo-methanocarbathymidine [North-methanocarbathymidine (N-MCT)], a thymidine analog with a pseudosugar ring locked in the northern conformation, which has previously been shown to block the replication of herpes simplex virus types 1 and 2. N-MCT inhibited KSHV virion production in lytically induced KSHV-infected BCBL-1 cells with a substantially lower 50% inhibitory concentration (IC50) than those of cidofovir (CDV) and ganciclovir (GCV) (IC50, mean +/- standard deviation: 0.08 +/- 0.03, 0.42 +/- 0.07, and 0.96 +/- 0.49 microM for N-MCT, CDV, and GCV, respectively). The reduction in KSHV virion production was accompanied by a corresponding decrease in KSHV DNA levels in the N-MCT-treated BCBL-1 cells, indicating that the compound blocked lytic KSHV DNA replication. A time- and dose-dependent accumulation of N-MCT-triphosphate (TP) was demonstrated in lytically induced BCBL-1 cells, while uninfected cells showed virtually no accumulation. The levels of N-MCT-TP were significantly decreased in the presence of 5'-ethynylthymidine, a potent inhibitor of herpesvirus thymidine kinase, resulting in the abrogation of anti-KSHV activity of N-MCT. N-MCT-TP more effectively blocked in vitro DNA synthesis by KSHV DNA polymerase with an IC50 of 6.24 +/- 0.08 microM (mean +/- standard deviation) compared to CDV-diphosphate (14.70 +/-2.47 microM) or GCV-TP (24.59 +/- 5.60 microM). Taken together, N-MCT is a highly potent and target-specific anti-KSHV agent which inhibits lytic KSHV DNA synthesis through its triphosphate metabolite produced in KSHV-infected cells expressing a virally encoded thymidine kinase. 相似文献
Objectives: Despite efforts to promote health equity, many American Indian and Alaska Native (AI/AN) populations, including older adults, experience elevated levels of depression. Although adverse childhood experiences (ACE) and social support are well-documented risk and protective factors for depression in the general population, little is known about AI/AN populations, especially older adults. The purpose of this study was to examine factors related to depression among a sample of AI older adults in the midwest.
Method: Data were collected using a self-administered survey completed by 233 AIs over the age of 50. The survey included standardized measures such as the Geriatric Depression Scale-Short Form, ACE Questionnaire, and the Multidimensional Scale of Perceived Social Support. Hierarchical multivariate regression analyses were conducted to evaluate the main hypotheses of the study.
Results: Two dimensions of ACE (i.e., childhood neglect, household dysfunction) were positively associated with depressive symptoms; social support was negatively associated with depressive symptoms. Perceived health and living alone were also significant predictors.
Conclusion: ACE may play a significant role in depression among AI/AN across the life course and into old age. Social support offers a promising mechanism to bolster resilience among AI/AN older adults. 相似文献