A dual CysLT1/2 antagonist attenuates allergen-induced airway responses in subjects with mild allergic asthma.

BACKGROUND: The cysteinyl leukotrienes (cysLTs) play a key role in the pathophysiology of asthma. In addition to functioning as potent bronchoconstrictors, cysLTs contribute to airway inflammation through eosinophil and neutrophil chemotaxis, plasma exudation, and mucus secretion. We tested the activity of the dual cysLT1/2 antagonist, ONO-6950, against allergen-induced airway responses. METHODS: Subjects with documented allergen-induced early (EAR) and late asthmatic response (LAR) were randomized in a three-way crossover study to receive ONO-6950 (200 mg) or montelukast (10 mg) or placebo q.d. on days 1-8 of the three treatment periods. Allergen was inhaled on day 7 two hours postdose, and forced expiratory volume in 1 s (FEV1 ) was measured for 7 h following challenge. Sputum eosinophils and airway hyperresponsiveness were measured before and after allergen challenge. The primary outcome was the effect of ONO-6950 vs placebo on the EAR and LAR. RESULTS: Twenty-five nonsmoking subjects with mild allergic asthma were enrolled and 20 subjects completed all three treatment periods per protocol. ONO-6950 was well tolerated. Compared to placebo, ONO-6950 significantly attenuated the maximum % fall in FEV1 and area under the %FEV1 /time curve during the EAR and LAR asthmatic responses (P < 0.05) and allergen-induced sputum eosinophils. There were no significant differences between ONO-6950 and montelukast. CONCLUSIONS: Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT1 blockade. Whether dual cysLT1/2 antagonism offers additional benefit for treatment of asthma requires further study.

Airway responsiveness to mannitol 24 h after allergen challenge in atopic asthmatics.

BACKGROUND: Airway responsiveness to indirect stimuli correlates positively with airway inflammation. In atopic asthmatics, allergen inhalation is associated with an influx of inflammatory cells and increased responsiveness to the direct-acting stimuli methacholine at 3 and 24 h after exposure. We have shown mannitol responsiveness decreases 3 h after allergen inhalation. The current investigation assessed mannitol responsiveness 24 h after allergen challenge. METHODS: Eleven mild atopic asthmatics completed allergen challenges on two separate occasions. In random order, methacholine or mannitol challenges were performed 24 h pre- and post-allergen challenge. Levels of fractional exhaled nitric oxide were also measured. RESULTS: Allergen challenge increased airway responsiveness to methacholine 24 h postchallenge; the geometric mean (95% CI) methacholine PC20 decreased from 5.9 mg/ml (1.8-19.4) to 2.2 mg/ml (0.81-5.89); P = 0.01. This coincided with a significant increase (P = 0.02) in FeNO levels. Conversely, allergen challenge decreased airway responsiveness to mannitol; geometric mean (95% CI) dose-response ratio was significantly higher after allergen exposure (57 mg/% FEV1 fall [27-121] to 147 mg/% FEV1 fall [57-379]; P = 0.03), and FeNO levels were not significantly increased (P = 0.054). CONCLUSION: Allergen-induced changes in airway responsiveness to direct and indirect stimuli are markedly different. The loss in responsiveness to mannitol is likely not explainable by a refractory state. The effect(s) of allergen exposure on airway responsiveness to indirect-acting stimuli require further investigation.

OX40L blockade and allergen-induced airway responses in subjects with mild asthma.

BACKGROUND: The OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli and plays an important role in the maintenance and reactivation of memory T effector cells. OBJECTIVE: We tested whether treatment with an anti-OX40L monoclonal antibody (MAb) would inhibit allergen-induced responses in subjects with asthma. METHODS: Twenty-eight mild, atopic asthmatic subjects were recruited for a double-blind, randomized, placebo-controlled, parallel-group trial (ClinicalTrials.gov identifier NCT00983658) to compare blockade of OX40L using a humanized anti-OX40L MAb to placebo-administered intravenously in 4 doses over 3 months. Allergen inhalation challenges were carried out 56 and 113 days after the first dose of study drug. The primary outcome variable was the late-phase asthmatic response. Other outcomes included the early-phase asthmatic response, airway hyperresponsiveness, serum IgE levels, blood and sputum eosinophils, safety and tolerability. RESULTS: Treatment with anti-OX40L MAb did not attenuate the early- or late-phase asthmatic responses at days 56 or 113 compared with placebo. In the anti-OX40L MAb treatment group, total IgE was reduced 17% from pre-dosing levels, and sputum eosinophils decreased 75% by day 113 (both P = 0.04). There was no effect of anti-OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups. CONCLUSION AND CLINICAL RELEVANCE: Pharmacological activity of anti-OX40L MAb was observed by decreases in serum total IgE and airway eosinophils at 16 weeks post-dosing, but there was no effect on allergen-induced airway responses. It is possible that the treatment duration or dose of antibody was insufficient to impact the airway responses.

Single-dose desloratadine and montelukast and allergen-induced late airway responses.

Montelukast and desloratadine synergistically inhibit the allergen-induced early asthmatic response. Montelukast also suppresses the allergen-induced late asthmatic response, but there are no reports on the effect of desloratadine or the combination on the allergen-induced late asthmatic response. Atopic asthmatics (n = 10) completed a multicentric randomised double-blind crossover study comparing single-dose placebo, 5 mg desloratadine, 10 mg montelukast and the combination administered 2 h prior to allergen inhalation challenge. Methacholine challenges were performed 24 h before and after allergen challenge. Exhaled nitric oxide measurements and sputum inflammatory cell counts were also carried out. All active treatments significantly decreased the late asthmatic response area under the curve. Combination therapy provided the greatest inhibition compared to desloratadine and montelukast. Montelukast was nonsignificantly better than desloratadine but not as effective as the combination. There was a trend towards a decrease in airway responsiveness following montelukast and combination. Montelukast, but not desloratadine or the combination, decreased exhaled NO levels 24 h after allergen. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed at 7 h with desloratadine and combination therapy, and at 24 h with montelukast and combination therapy. Single-dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment.

Calculation of provocative concentration causing a 20% fall in FEV(1): comparison of lowest vs highest post-challenge FEV(1).

BACKGROUND: Considerable, unexamined controversy exists surrounding the use of the highest vs the lowest FEV(1) for calculating the provocative concentration causing a 20% fall in FEV(1) (PC(20)) during direct bronchoprovocation challenges. OBJECTIVE: To compare the PC(20) calculated using the lowest FEV(1) post-diluent and post-histamine/methacholine vs the PC(20) calculated using the highest FEV(1) post-diluent and post-histamine/methacholine. METHOD: Retrospective analysis of 225 challenges: 75 research methacholine challenges, 75 research histamine challenges, and 75 clinical methacholine challenges. For each test, the PC(20) was calculated twice, first using the lowest post-diluent FEV(1) to the lowest post-histamine/methacholine FEV(1), and then using the highest to the highest. RESULTS: The intraclass correlation coefficients for methacholine research, histamine research, and methacholine clinic challenges were 0.99, 0.98, and 0.95, respectively. The PC(20) calculated using the lowest to lowest FEV(1) was slightly and significantly lower in all three groups (paired t test p < 0.0001). CONCLUSIONS: The PC(20) values calculated using the highest FEV(1) are almost identical to the PC(20) values calculated using the lowest FEV(1). The difference, although clinically irrelevant, holds statistical significance.

Regular inhaled salbutamol : effect on airway responsiveness to methacholine and adenosine 5'-monophosphate and tolerance to bronchoprotection.

OBJECTIVE: Regular treatment with inhaled beta(2)-agonists increases airway responsiveness consistently to indirect bronchoconstrictors (allergen, exercise, hypertonic saline solution, etc) and inconsistently to direct bronchoconstrictors (histamine, methacholine). Studies demonstrating tolerance to beta(2)-agonist bronchoprotection against the indirect bronchoconstrictor adenosine 5'-monophosphate (AMP) have not examined changes in baseline AMP responsiveness. This study assessed the effect of regular salbutamol on AMP and methacholine responsiveness and on tolerance to bronchoprotection. DESIGN: Double-blind, randomized, crossover study. SETTING: University hospital bronchoprovocation laboratory. PATIENTS: Fourteen atopic asthmatic subjects with FEV(1) > 65% predicted, and methacholine provocative concentration causing a 20% fall in FEV(1) (PC(20)) < 8 mg/mL. INTERVENTIONS: Salbutamol, 100 microg, and placebo inhalers, two puffs qid, each for 10 days. MEASUREMENTS: Methacholine PC(20) and AMP PC(20) measured 12 h after blinded inhaler after each treatment period. Methacholine PC(20) and AMP PC(20) repeated 10 min after salbutamol, 200 microg (eight subjects). RESULTS: There was no difference between placebo and salbutamol treatment in geometric mean methacholine PC(20) (0.85 mg/mL vs 0.82 mg/mL, p = 0.86) or AMP PC(20) (22 mg/mL vs 17.4 mg/mL, p = 0.21; n = 14). The acute bronchoprotective effect of salbutamol was greater vs. AMP than vs methacholine (5.1 doubling concentrations vs. 3.5 doubling concentrations, p = 0.06) and loss of protective effect of salbutamol (mean +/- SD) was greater vs AMP than vs. methacholine (2.4 +/- 0.33 doubling concentration loss vs 0.8 +/- 0.21 doubling concentration loss, p = 0.008; n = 8). CONCLUSION: Regular salbutamol (mean +/- SD) treatment did not enhance airway responsiveness to either the indirect bronchoconstrictor AMP or the direct bronchoconstrictor methacholine. Compared to its effect on methacholine, salbutamol had a greater acute protective effect vs AMP and produced greater loss of protection vs AMP when used regularly.

Prone infant sleeping despite the "Back to Sleep" campaign.

OBJECTIVES: To determine sleep position variation during the first 6 months of life and to identify risk factors for prone sleeping. DESIGN: Cohort study of healthy term newborns recruited from November 1995 to September 1996 and followed up to age 6 months. Pediatricians were surveyed about sleep position advice. At recruitment, all parents were instructed to avoid prone sleeping. Parents were telephoned at 1 week and then monthly to ensure that they recorded sleep position. Investigators were unaware of sleep position until the infant was 6 months of age, when sleep log data and reasons for sleep position choice were ascertained. SETTING: Practice-based study conducted by the Children's National Medical Center Pediatric Research Network, Washington, DC. PARTICIPANTS: A total of 402 consecutive healthy term newborns followed up by a Pediatric Research Network pediatrician were enrolled. Exclusion criteria were prematurity, a serious medical condition, and absence of a telephone. Of the 402 enrolled newborns, 348 (86.6%) completed the study. RESULTS: Only 34.0% of infants maintained a consistent sleep position. Prone sleeping increased from 12.2% at birth to 32.0% at 6 months. One third of pediatricians discussed sleep position beyond the newborn period. The following were associated (P<.05) with prone sleeping: male sex, lower maternal education level, single marital status, having siblings, and black race. Perceived infant comfort was the main reason for prone sleeping. CONCLUSIONS: Most newborns are placed by parents in nonprone sleep positions. Pediatricians need to consistently reinforce the "Back to Sleep" message when the infants are 2 to 4 months of age because this is the most likely time that they are switched to prone sleeping and the highest risk period of sudden infant death syndrome. Parents should not use prone sleeping as a means of comforting infants.

Severe early onset preeclampsia secondary to bilateral ureteral obstruction reversed by stenting.

BACKGROUND: Severe early onset preeclampsia might be reversed by correction of an underlying pathophysiologic condition. CASE: A 22-year-old nullipara with a history of antivesicoureteral reflux surgery in childhood presented at 23 weeks' gestation with severe headaches, hypertension, proteinuria, edema, and acute renal failure. Severe preeclampsia was diagnosed, and bilateral distal ureteral obstruction was documented by cystoscopy, fluoroscopy, and retrograde pyelography. Bilateral ureteral stent placement completely resolved the preeclampsia and prolonged pregnancy until term. CONCLUSION: Pregnant women with a history of antireflux surgery in childhood might be at risk for acute renal failure and severe preeclampsia caused by bilateral ureteral obstruction. Ureteral stent placement might reverse obstruction, renal failure, and preeclampsia.

Combined cholecystectomy and radical genitourinary cancer surgery.

We have routinely performed simultaneous cholecystectomy in patients with cholelithiasis undergoing selected radical genitourinary cancer surgery. A total of 31 patients have undergone cholecystectomy at the time of radical nephrectomy (25), radical cystectomy (5), and radical prostatectomy (1). Operative time was increased twenty-five to forty-five minutes. There was no significant increase in blood loss, postoperative total bilirubin, or number of complications. No complications were directly attributable to the cholecystectomy except for 1 patient who had prolonged drainage from a closed suction drain in the gallbladder fossa. We conclude that concomitant cholecystectomy at the time of radical genitourinary cancer surgery does not significantly increase morbidity and recommend that it be performed in the presence of cholelithiasis.

Serum soluble interleukin 2 receptor levels in erythrodermic cutaneous T-cell lymphoma correlate with response to photopheresis-based treatment.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) comprises a spectrum of presentations, including erythroderma, pruritus, lymphadenopathy, and circulating atypical lymphocytes. Photopheresis is an extracorporeal treatment in which white blood cell concentrates are subjected to UV irradiation when the serum methoxypsoralen level is above 50 ng/mL. Of patients with CTCL, those with erythroderma have been most responsive to this therapy. In some conditions, including certain malignant hematologic neoplasms, serum soluble interleukin 2 receptor levels (SIL2R) correlate with disease activity. We sought to determine whether serum SIL2R levels correlated with disease activity in six erythrodermic patients with CTCL treated primarily with photopheresis. We measured SIL2R levels in five patients with stage III or greater erythrodermic CTCL and one with stage IIa CTCL. We compared SIL2R values with clinical course, skin scores, CD4/CD8 ratios, peripheral white blood cell counts, and Sézary cell counts, using Pearson correlation coefficients. OBSERVATIONS: The SIL2R levels correlated with clinical course and skin scores, even when controlled for other factors noted above. CONCLUSION: Data preliminarily suggest that serum SIL2R levels may be useful indicators of disease activity in erythrodermic CTCL patients treated with photopheresis.

New concepts in the treatment of stage D1 adenocarcinoma of the prostate.

Stage D1 disease will be encountered in 20 per cent of patients by those who treat prostate cancer. There is marked heterogeneity among cancers discovered at this stage, with 5-year disease-free survival rates ranging from 0 to 95 per cent. Generally, when prostate cancer has escaped the confines of the gland, metastasis occurs, and widespread systemic disease prevails. Any significant chance for long-term cure will then depend on systemic therapy. From maturing data in retrospective reviews, preliminary data from prospective trials, and recent well-conducted animal studies, chemotherapy and hormonal deprivation appear most effective when tumor volumes are the smallest. This evidence supports the removal of all cancer possible and the early institution of systemic treatment. Caution must be exercised in extrapolating the aforementioned evidence to include cases of more extensive prostate cancer (i.e., patients with bulky pelvic or retroperitoneal disease, distant metastasis, or significant elevation of serum markers). It is doubtful that "debulking" with removal of the prostate and lymph nodes will provide any justifiable advantages in these patients. Whether removal of the prostate affords any local palliative benefit is an issue for debate. Certainly, the primary tumor, if left untreated, will progress locally and cause symptoms necessitating further procedures in more than half these patients, whereas the incidence of local recurrence and the adverse effects of these recurrences in patients with D1 disease after radical prostatectomy and adjuvant therapy is less than 10 per cent. Surgical refinements coupled with acceptably low morbidity now associated with radical prostatectomy have led some authors to endorse the palliative benefits of removing the primary tumor in selected patients. The purpose of this article is not to endorse or disparage the aggressive treatment of patients with stage D1 prostate cancer. The evidence suggests that if long-term survival is the endpoint used to compare treatment groups, then to date no treatment option offers significant advantages. On the contrary, if progression rates or disease-free survival are compared, then cytoreductive surgery and early systemic adjuvant treatment (testosterone deprivation or chemotherapy) provides significant advantages for selected patients with stage D1 disease. Although ploidy analysis, receptor mapping, and oncogene assays are promising, today, there is no practical way to identify patients who will benefit most from multimodality treatment approaches.(ABSTRACT TRUNCATED AT 400 WORDS)

Do clerkship experiences affect medical students' attitudes toward chronically ill patients?

PURPOSE: To measure changes in medical students' attitudes toward chronically ill patients, and to identify experiences, specifically during clerkships, that contributed to students' attitudes. METHOD: A cohort of students from five U.S. medical schools voluntarily participated in three surveys longitudinally administered before and after required clinical rotations. The first two questionnaires were identical and asked for demographic information and pre-matriculation experiences with chronically ill patients. The third was modified to include questions about clinical experiences with chronically ill patients. Responses from the first and third questionnaires were linked for analysis. RESULTS: A total of 502 of 695 students (69%) completed both the first and the third questionnaires. Many students (36%) had had pre-matriculation experiences with chronic illness. After clinical training, 25% of the respondents stated that they would seek another career specialty if the incidence of chronically ill patients increased in their chosen field, compared with the 9% who responded so before clinical training (p <.001). While 73% of the students had favorable perceptions toward chronically ill patients, and 91% felt involved in care, significantly fewer students (p <.01) had had positive patient care experiences when working with residents (57%) and attendings (59%). Gender, age, prior experiences, and school site were not associated with attitudinal changes. CONCLUSION: Students begin medical school with positive attitudes toward caring for chronically ill patients, but this perception depreciates with clinical experience, which may affect specialty decisions. Contributing factors may include adequate role modeling by residents and attendings and a perceived discrepancy in the quality of care patients receive.

Longevity of patients born with myelomeningocele.

There are limited data concerning the life expectancy for individuals born with myelomeningocele (MM), with and without hydrocephalus. To ascertain such data was our first purpose. We have selected all patients with MM in our computer database, The Patient Data Management System (PDMS/fx). Data were transferred to Excel for primary and SPSS/PC for final analysis by Kaplan-Meier life survival curves. Of the 1,054 patients with MM in the Birth Defects Clinic and the University of Washington Medical Center (UWMC) of Seattle, 505 are now over the age of 21 (391) or have died (114). Follow-up information was available since 1994 for 132, 62% of whom we have had contact within the past 2 years. The second purpose was to identify potential health factors associated with long-term outcome of patients with MM. Patient variables chosen as relevant to survival included hydrocephalus, treatment before or after 1975, and health maintenance determined by outcome for those receiving care within the last 5 years or those last seen before. Age at last appointment and reason for visit were determined in order to identify age-specific health care needs of the adult population. Survival and medical needs were obtained from the UWMC's computer database, Mindscape, and by telephone survey for adult patients not seen in the last 2 years. Death is more frequent earlier in life for those MM patients with hydrocephalus. Ordinary degenerative disorders affect MM patients earlier in life than normals. Our data extend life expectancy for patients with MM and hydrocephalus to age 40 years with some reliability for those treated from 1957 to 1974, but only 24 years for those treated with modern techniques after 1974. More data is needed to determine long-term survival.

Comparison of primary closure of incisional hernias in horses with and without the use of prosthetic mesh support.

REASONS FOR PERFORMING STUDY: Repair of incisional hernias in horses has been described previously; however, this report describes the outcome of primary closure of incisional hernias in a large number of horses and compares these results with those of mesh implantation. OBJECTIVE: To report the perioperative care, complications and long-term outcome of primary closure of incisional hernias in horses and to compare these results with a second population of horses in which prosthetic mesh was used. METHODS: Medical records of horses undergoing an incisional herniorrhaphy between 1998 and 2009 were reviewed. Information obtained included case details, factors from the initial surgery that contributed to the hernia formation, method of hernia repair and outcome. Comparisons between horses with and without mesh were made using logistic regression. RESULTS: Thirty-eight horses with primary closure and 9 horses with mesh implantation met inclusion criteria. Long-term follow-up for cases in which a mesh was not used was available for 25 cases; of these, 21 horses (84%) had a normal cosmetic appearance and 4 (16%) had a visible defect. There was no significant difference between the 2 repair methods in terms of age, sex, breed, weight, size of the hernia, number of defects, timing of the repair or cosmetic outcome. Horses in which a mesh was used had significantly longer duration of surgery and hospitalisation, and were significantly more likely to develop post operative complications while having a longer duration of convalescence prior to return to use. CONCLUSIONS: Primary apposition of incisional hernias in horses without the use of mesh support appears to result in a good cosmetic outcome while avoiding the complications associated with mesh implantation in this population of horses. POTENTIAL RELEVANCE: Surgical time, duration of hospitalisation, and post operative complications may be reduced by using this technique of primary repair and avoiding mesh implantation.