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Background: There are currently no licensed vaccines available for prevention of botulism in humans. The vaccination is not desirable due to expanding therapeutic indications of botulinum toxins. The only available specific treatment for botulism is antitoxin to remove circulating toxin, thus, preventing further neuronal damage. BAT® (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)-(Equine)) has been developed and its therapeutic efficacy evaluated against botulinum neurotoxin serotype A (BoNT/A) in Rhesus macaques., Methods and Findings: In a post-exposure prophylaxis (PEP) study, animals were exposed to 4x LD50/kg of BoNT/A and administered intravenously with either BAT (1x or 0.1x scaled human dose), or placebo at 4 hours post-exposure. The animals were monitored for 14 days. For the therapeutic intervention studies, animals were exposed to a 1.7x LD50/kg of BoNT/A and treated intravenously with either placebo or BAT at a 1x scaled human dose at the onset of clinical signs. Animals were monitored on an hourly basis for 14 or 21 days. In the PEP study, all animals tolerated equine based antitoxin without any adverse clinical signs. A 100% survival was observed in groups treated with the BAT compared to 0% survival in those treated with the placebo (p<0.001, Fisher's exact test). BAT antitoxin prevented the development of signs of neurotoxicity of botulinum toxin. In a therapeutic study, treatment with the BAT at scaled 1x human dose after the onset of clinical signs significantly enhanced survival compared to the placebo (46.6% vs. 0%, p<0.0001, Fisher's exact test). Additionally, treatment with the BAT delayed the progression of signs (muscular weakness, respiratory distress, oral/nasal discharge) of toxin intoxication and reduced the severity of the disease., Conclusions: A single dose of BAT, when administered to symptomatic monkeys, resulted in a statistically significant survival benefit compared to the placebo. Additionally, BAT completely protected monkeys from the clinical signs of intoxication and subsequent death when administered as PEP treatment. These data in part supported the licensure of BAT under the Animal Rule in the United States by the Food and Drug Administration.

Objective: To assess barriers to the counseling of obese patients and identify pharmacists' characteristics associated with these barriers., Design: Cross-sectional mail survey., Setting: Texas., Participants: 139 community pharmacists., Intervention: Self-administered questionnaire., Main Outcome Measures: Respondents' perceived barriers to pharmacists' counseling of obese patients., Results: The top three barriers to counseling included lack of time (76.8%), lack of patient demand or expectations (55.8%), and lack of reimbursement/compensation (49.3%). Pharmacists indicated that they rarely to sometimes counseled obese patients and were somewhat comfortable with counseling about obesity management. They perceived obesity management strategies to be somewhat effective in weight loss, but were neutral regarding their confidence in achieving positive outcomes with counseling. Pharmacists who were more experienced were more likely to indicate that obesity is controllable without medications. Those who considered obesity controllable without medications were significantly more likely to view the various obesity management strategies as less effective, compared with those who did not share this belief. Pharmacists who viewed lack of privacy as a barrier were significantly less confident in achieving positive outcomes as a result of counseling. Creating awareness among patients about pharmacists' ability to counsel was perceived as most important in overcoming barriers., Conclusion: Pharmacists identified several barriers to counseling of obese patients. Pharmacists' demographics and beliefs about obesity were significantly associated with their perceived barriers.

Background: Obesity is reaching an epidemic proportion in the US. Nearly two-thirds (64.7%) of US adults are overweight or obese. Given the myriad of issues related to the management of obesity, community pharmacists can facilitate weight loss among their patients., Objective: To identify factors that influence the frequency of counseling obese patients by community pharmacists., Methods: A mail survey was sent to a random sample of 400 Texas community pharmacists. The questionnaire collected information on frequency of counseling obese patients, perceived comfort level with counseling obese patients, perceived effectiveness of various obesity treatments, and perceived confidence in achieving positive outcomes as a result of counseling. Demographic information was also collected. Descriptive statistics, correlational analyses, and t-tests were used to examine the data., Results: A usable response rate of 35.2% was obtained (139 completed surveys out of 395 assumed delivered). Overall, pharmacists counseled patients rarely to sometimes about various aspects of obesity management. Correlational analyses revealed that pharmacists' frequency of counseling about obesity management was significantly and positively associated with their comfort level with counseling obese patients (r = 0.47; p < 0.001). Higher levels of confidence in achieving positive outcomes as a result of counseling (r = 0.39; p < 0.001) and higher levels of perceived effectiveness of obesity management options (r = 0.18; p = 0.037) were also significantly associated with higher levels of counseling about obesity management., Conclusions: Obesity counseling by pharmacists was positively correlated with their perceived comfort with counseling obese patients, confidence in achieving positive outcomes, and effectiveness of obesity management options.

Menstrual migraines are a treatment challenge for both the migraineur and the health care professional. Although some women with menstrual migraines may respond to acute and preventive therapies for nonmenstrual migraines, others continue to suffer from refractory menstrual migraines. These women may respond to hormonal interventions, which may reduce the frequency of menstrual migraines, thereby lessening the need for abortive migraine therapies, decreasing migraine-related disability, and improving quality of life. Menstrual migraines have a distinct pathophysiology that differs from menstrual-related migraines. Published studies have shed light on the effectiveness of a variety of hormonal interventions, including oral contraceptives, which may be administered with an extended-dosing strategy; estrogen replacement therapy; selective estrogen receptor modifiers; danazol; and leuprolide.

Objectives: After an initial vasodilator response to alkalosis, many children with pulmonary hypertension exhibit marked pulmonary vascular reactivity despite continued alkalosis therapy. This study sought to a) identify the mediator of alkalosis-induced pulmonary vasodilation in isolated lamb lungs; b) determine whether alkalosis-induced pulmonary vasodilation decreases over time in this model; and c) determine whether alkalosis enhanced vascular reactivity to subsequent pressor stimuli., Design: Prospective, interventional study., Subjects: Isolated perfused lungs from 1-month-old lambs., Interventions: Hypocarbic alkalosis, hypoxia, and infusion of the thromboxane mimetic agent U46619, Measurements and Main Results: Pulmonary artery pressure was measured at constant flow, so a change in pressure reflects change in resistance. Hypoxic pulmonary artery pressure was compared after 20 and 100 mins of hypocarbic alkalosis or normocarbia in control and cyclooxygenase-inhibited lungs. Pulmonary artery dose responses to U46619 were then measured in control lungs. Responses to hypoxia and U46619 were also compared after 60-80 mins of hypocarbic or normocarbic normoxia. Hypocarbic alkalosis acutely reduced hypoxic pulmonary vascular resistance, and this was sustained for at least 100 mins. Cyclooxygenase inhibition blocked this vasodilation, suggesting that it was mediated by dilator prostaglandins. However, subsequent reactivity to U46619 was enhanced in hypoxic alkalotic lungs, and both hypoxia and U46619 caused significant vasoconstriction in normoxic alkalotic lungs., Conclusions: Alkalosis caused sustained vasodilation when pulmonary vascular resistance was high but either failed to attenuate or enhanced vascular reactivity to subsequent pressor stimuli.

Developmental changes in modulation of pulmonary vasomotor tone by endothelium-derived nitric oxide (EDNO) may reflect maturational differences in endothelial synthesis of and/or vascular smooth muscle response to nitric oxide. This study sought to determine whether pulmonary vascular sensitivity and responsiveness to nitric oxide change during newborn development, and whether this is related to changes in guanylate cyclase activity. Pulmonary artery dose-responses to inhaled nitric oxide (iNO, 0.25-100 parts per million) were measured in hypoxic, indomethacin-treated, isolated lungs from 1-day (1-d)- and 1-month (1-m)-old lambs. The lungs of 1-m-old lambs were ventilated with 4% (oxygen) O2, and lungs of 1-d-old lambs were ventilated with either 4% or 7% O2 in order to achieve similar stimuli or vasomotor tone. Cyclic guanosine monophosphate (cGMP) concentrations in the perfusate were measured at iNO concentrations of 0, 5, and 100 parts per million (ppm). Basal and stimulated pulmonary guanylate cyclase activity was also measured in lung extracts in vitro. The effects of iNO were similar in both 1-d groups, even though baseline hypoxic tone was significantly higher in 1-d lungs ventilated with 4% O2 than with 7% O2. Furthermore, both the 1-d 7% O2 and 1-d 4% O2 lungs exhibited greater responsiveness and sensitivity to iNO than 1-m lungs. Perfusate cGMP concentrations and soluble guanylate cyclase activity were higher under stimulated than basal conditions, but neither differed statistically between 1 d and 1 m. These data suggest that pulmonary vascular responsiveness and sensitivity to nitric oxide decrease with age, but the mechanisms underlying these maturational changes require further investigation.

Effective attenuation of pulmonary vasoconstriction is essential during early postnatal development when increased pulmonary vascular resistance (PVR) may lead to a resumption of right-to-left shunting across fetal channels. In addition, modulation of venous resistance contributes to normal lung fluid balance. This study was designed to identify the relative modulating effects of endothelium-derived nitric oxide (EDNO) and dilator prostaglandins (PG) on normoxic and hypoxic pulmonary vasomotor tone in young newborns. Total and segmental PVR were measured using inflow-outflow and double occlusion techniques in isolated lungs of 6-h-old lambs studied under control conditions or after blocking PG and/or EDNO synthesis with indomethacin and/or N omega-nitro-L-arginine, respectively. During normoxia, both indomethacin and N omega-nitro-L-arginine were required to increase total PVR, but EDNO appeared to have the greater modulating effect. Indomethacin markedly enhanced hypoxic pulmonary vasoconstriction of large and small arteries and small veins, whereas N omega-nitro-L-arginine caused a lesser, but significant, increase in hypoxic pulmonary vasoconstriction of small arteries and veins, suggesting that dilator PG played the dominant modulating role during hypoxia. In addition, PG synthesis appeared to be enhanced after inhibition of EDNO synthesis. In contrast, indomethacin caused a decrease in venous resistance, suggesting that constrictor prostanoids had a greater effect than dilator PG on this segment. EDNO had a modest modulating effect on venous resistance in these lungs. These data suggest that dilator PG and EDNO exert complementary effects in attenuating total and segmental PVR during normoxia and hypoxia in 6-hold lamb lungs.

We hypothesized that maturational changes in both prostaglandin and endothelium-derived nitric oxide (EDNO) activity contribute to developmental changes in endothelium-dependent relaxation of newborn pulmonary arteries. Responses to endothelium-dependent vasodilators acetylcholine, bradykinin, and calcium ionophore A-23187 were determined in phenylephrine-constricted third- and fourth-generation (1- to 2-mm-diameter) pulmonary artery rings from 2-day (2d)- and 1-mo (1m)-old lambs under control conditions (Con), after inhibition of EDNO synthesis with N omega-nitro-L-arginine (L-NNA), after inhibition of prostanoid synthesis with meclofenamate (Mec), or both modulators with both inhibitors. Endothelium-independent responses to sodium nitroprusside (SNP) were also measured in Con rings. Endothelium-dependent relaxation was greater in 2d than 1m Con rings, particularly at high concentrations when an increase in tension occurred in 1m rings. L-NNA attenuated endothelium-dependent relaxation more in 2d rings, and SNP caused greater relaxation in 2d rings. However, Mec abolished all age-related differences by attenuating relaxation in 2d rings and constriction in 1m rings. These data suggest that developmental changes in endothelium-dependent responses of ovine pulmonary artery rings reflect both a decrease in EDNO activity and maturational differences in the relative influence of dilator and constrictor prostanoids.

We developed an instrument to assess comprehension of informed consent information among 275 adults entering one of four ambulatory trials. At the conclusion of trial enrollment, subjects rated their understanding of the information presented and completed the Deaconess Informed Consent Comprehension Test (DICCT). Subjects completed the vocabulary subtest of the revised Weschler Adult Intelligence Scale (WAIS-R) and the reading subtest of the revised Wide Range Achievement Test (WRAT-R). The DICCT for 50 subjects was scored by 2 blinded investigators. Interrater agreement was 0.84 (df = 49, p < 0.001). To investigate the DICCT's potential validity, its scores were correlated with WAIS-R vocabulary scores (r = 0.44, df = 199, p < 0.01) and WRAT-R reading scores (r = 0.39, df = 268, p < 0.01). Understanding of consent information was rated as thorough by 70% of subjects. The mean +/- SD DICCT score was 20.4 +/- 3.9. The DICCT is a reliable instrument to assess comprehension of informed consent information. There is preliminary evidence for the scale's validity. The subjects believed that they had greater understanding of study information than was shown by the DICCT.

Both increases and decreases in endothelium-derived nitric oxide (EDNO) activity have been described in the developing pulmonary vasculature. We hypothesized that differences in baseline vasomotor tone and/or oxygen tension may contribute to this variability. Pulmonary arterial dose responses to endothelium-dependent and -independent vasodilators acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were measured in indomethacin-treated lungs of 1- to 2-day-old (2D) and 1-mo-old (1M) lambs. During 4% O2 ventilation, baseline pulmonary vascular resistance (PVR) and the dilator response to both ACh and SNP were greater in 2D lungs. However, when baseline PVR values were matched at both ages during either hypoxia or infusion of a thromboxane mimetic under normoxic conditions, developmental differences in ACh-induced vasodilation were minimal. Furthermore, hypoxia itself did not alter the responses to ACh in 2D lungs. In contrast, SNP caused greater vasodilation in 2D than in 1M lungs regardless of baseline PVR. These data and studies suggest that whereas high PVR enhances EDNO synthesis, responsiveness to ENDO decreases as synthesis of ENDO increases in developing lungs studied under basal conditions.