Search

This study compared transcutaneous oxygen tension (TcpO2) in subjects with paraplegia and pressure ulcers (PU), those with paraplegia and no pressure ulcer (NPU), and ambulatory controls. TcpO2 was measured using a surface-electrode monitoring system, recorded at 1-min intervals for 5 min and averaged. Mean TcpO2 was significantly lower in the PU than the NPU and control groups (23.53 +/- 1.83 vs. 58.93 +/- 2.53 and 79.70 +/- 6.77 mmHg, respectively, p<0.05). In a PU subgroup (n=4) mean TcpO2 of the pressure ulcer and nonpressure ulcer sides (trochanter or ischium) were significantly different (21.05 +/- 2.98 vs. 67.65 +/- 2.11 mmHg, respectively, p<0.001). Additionally, the NPU group demonstrated significantly lower TcpO2 than the controls. PUs had a greater reduction in TcpO2 levels relative to controls than NPUs. No association was found between TcpO2 and duration of injury, completeness of lesion, or smoking history. Thus, TcpO2 may be an effective method to identify individuals who are susceptible to pressure ulcers. The further attenuation of TcpO2 observed in the PU group may be useful to help predict whether ulcers will heal with local care or will require additional treatment. [ABSTRACT FROM AUTHOR]

Background: Patients with sinonasal malignancy (SNM) present with significant sinonasal quality of life (QOL) impairment. Global sinonasal QOL as measured by the 22-item Sinonasal Outcomes Test (SNOT-22) has been shown to improve with treatment. This study aims to characterize SNOT-22 subdomain outcomes in SNM., Methods: Patients diagnosed with SNM were prospectively enrolled in a multi-center patient registry. SNOT-22 scores were collected at the time of diagnosis and through the post-treatment period for up to 5 years. Multivariable regression analysis was used to identify drivers of variation in SNOT-22 subdomains., Results: Note that 234 patients were reviewed, with a mean follow-up of 22 months (3 months-64 months). Rhinologic, psychological, and sleep subdomains significantly improved versus baseline (all p < 0.05). Subanalysis of 40 patients with follow-up at all timepoints showed statistically significant improvement in rhinologic, extra-nasal, psychological, and sleep subdomains, with minimal clinically important difference met between 2 and 5 years in sleep and psychological subdomains. Adjuvant chemoradiation was associated with worse outcomes in rhinologic (adjusted odds ratio (5.22 [1.69-8.66])), extra-nasal (2.21 [0.22-4.17]) and ear/facial (5.53 [2.10-8.91]) subdomains. Pterygopalatine fossa involvement was associated with worse outcomes in rhinologic (3.22 [0.54-5.93]) and ear/facial (2.97 [0.32-5.65]) subdomains. Positive margins (5.74 [2.17-9.29]) and surgical approach-combined versus endoscopic (3.41 [0.78-6.05])-were associated with worse psychological outcomes. Adjuvant radiation (2.28 [0.18-4.40]) was associated with worse sleep outcomes., Conclusions: Sinonasal QOL improvements associated with treatment of SNM are driven by rhinologic, extra-nasal, psychological, and sleep subdomains., (© 2024 ARS‐AAOA, LLC.)

Objective: To examine the impact of increased body mass index (BMI) on (1) tracheotomy timing and (2) short-term surgical complications requiring a return to the operating room and 30-day mortality utilizing data from the Multi-Institutional Study on Tracheotomy (MIST)., Methods: A retrospective analysis of patients from the MIST database who underwent surgical or percutaneous tracheotomy between 2013 and 2016 at eight institutions was completed. Unadjusted and adjusted logistic regression analyses were used to assess the impact of obesity on tracheotomy timing and complications., Results: Among the 3369 patients who underwent tracheotomy, 41.0% were obese and 21.6% were morbidly obese. BMI was associated with higher rates of prolonged intubation prior to tracheotomy accounting for comorbidities, indication for tracheotomy, institution, and type of tracheostomy (p = 0.001). Morbidly obese patients (BMI ≥35 kg/m 2 ) experienced a longer duration of intubation compared with patients with a normal BMI (median days intubated [IQR 25%-75%]: 11.0 days [7-17 days] versus 9.0 days [5-14 days]; p < 0.001) but did not have statistically higher rates of return to the operating room within 30 days (p = 0.12) or mortality (p = 0.90) on multivariable analysis. This same finding of prolonged intubation was not seen in overweight, nonobese patients when compared with normal BMI patients (median days intubated [IQR 25%-75%]: 10.0 days [6-15 days] versus 10.0 days [6-15 days]; p = 0.36)., Conclusion: BMI was associated with increased duration of intubation prior to tracheotomy. Although morbidly obese patients had a longer duration of intubation, there were no differences in return to the operating room or mortality within 30 days., Level of Evidence: 3 Laryngoscope, 134:4674-4681, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Ambu® aScope™ is a disposable flexible videoscope used for a wide range of medical procedures. However, adverse events associated with this device can occur. The Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database was explored for patient-related adverse events associated with Ambu® aScope™ use between January 1, 2000 and December 15, 2023. Search terms included "Ambu" and "Ascope." Thirty unique adverse events were identified. Twenty-one of the events were associated with patient injury, and 9 with device malfunction. Eight patient-reported problems were documented as foreign bodies, 3 events as airway obstruction, desaturation, or hypoxic events, and 1 event as anxiety/cardiac arrest. The remaining 18 reported insufficient information other than associated with patient injury. We found that Ambu® aScope™ flexible nasolaryngoscopes and bronchoscopes are a common and effective tool for airway evaluations that may infrequently serve as a rare form of foreign body with potentially life-threatening consequences., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Purpose: Large language models continue to dramatically change the medical landscape. We aimed to explore the utility of ChatGPT in providing accurate, actionable, and understandable generative medical translations in English, Spanish, and Mandarin pertaining to Otolaryngology., Methods: Responses of GPT-4 to commonly asked patient questions listed on official otolaryngology clinical practice guidelines (CPG) were evaluated with the Patient Education materials Assessment Tool-printable (PEMAT-P.) Additional critical elements were identified a priori to evaluate ChatGPT's accuracy and thoroughness in its responses. Multiple fluent speakers of English, Mandarin, and Spanish evaluated each response generated by ChatGPT., Results: Total PEMAT-P scores differed between English, Mandarin, and Spanish GPT-4 generated responses depicting a moderate effect size of language, Eta-Square 0.07 with scores ranging from 73 to 77 (P-value = 0.03). Overall understandability scores did not differ between English, Mandarin, and Spanish depicting a small effect size of language, Eta-Square 0.02 scores ranging from 76 to 79 (P-value = 0.17), nor did overall actionability scores Eta-Square 0 score ranging 66-73 (P-value = 0.44). Overall a priori procedure-specific responses similarly did not differ between English, Spanish, and Mandarin Eta-Square 0.02 scores ranging 61-78 (P-value = 0.22)., Conclusion: GPT-4 produces accurate, understandable, and actionable outputs in English, Spanish, and Mandarin. Responses generated by GPT-4 in Spanish and Mandarin are comparable to English counterparts indicating a novel use for these models within Otolaryngology, and implications for bridging healthcare access and literacy gaps., Level of Evidence: IV., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Tracheotomies are frequently performed by nonotolaryngology services. The factors that determine which specialty performs the procedure are not defined in the literature but may be influenced by tracheotomy approach (open vs percutaneous) and other clinicodemographic factors., Objective: To evaluate demographic and clinical characteristics associated with tracheotomies performed by otolaryngologists compared with other specialists and to differentiate those factors from factors associated with use of open vs percutaneous tracheotomy., Design, Setting, and Participants: This multicenter, retrospective cohort study included patients aged 18 years or older who underwent a tracheotomy for cardiopulmonary failure at 1 of 8 US academic institutions between January 1, 2013, and December 31, 2016. Data were analyzed from September 2022 to July 2023., Exposure: Tracheotomy., Main Outcomes and Measures: The primary outcome was factors associated with an otolaryngologist performing tracheotomy. The secondary outcome was factors associated with use of the open tracheotomy technique., Results: A total of 2929 patients (mean [SD] age, 57.2 [17.2] years; 1751 [59.8%] male) who received a tracheotomy for cardiopulmonary failure (652 [22.3%] performed by otolaryngologists and 2277 [77.7%] by another service) were analyzed. Although 1664 of all tracheotomies (56.8%) were performed by an open approach, only 602 open tracheotomies (36.2%) were performed by otolaryngologists. Most tracheotomies performed by otolaryngologists (602 of 652 [92.3%]) used the open technique. Multivariable regression analysis revealed that self-reported Black race (odds ratio [OR], 1.89; 95% CI, 1.52-2.35), history of neck surgery (OR, 2.71; 95% CI, 2.06-3.57), antiplatelet and/or anticoagulation therapy (OR, 1.74; 95% CI, 1.29-2.36), and morbid obesity (OR, 1.54; 95% CI, 1.24-1.92) were associated with greater odds of an otolaryngologist performing tracheotomy. In contrast, history of neck surgery (OR, 1.36; 95% CI, 0.96-1.92), antiplatelet and/or anticoagulation therapy (OR, 0.80; 95% CI, 0.56-1.14), and morbid obesity (OR, 0.94; 95% CI, 0.74-1.19) were not associated with undergoing open tracheotomy when performed by any service, and Black race (OR, 0.56; 95% CI, 0.44-0.71) was associated with lesser odds of an open approach being used. Age-adjusted Charlson Comorbidity Index score greater than 4 was associated with greater odds of both an otolaryngologist performing tracheotomy (OR, 1.26; 95% CI, 1.03-1.53) and use of the open tracheotomy technique (OR, 1.48, 95% CI, 1.21-1.82)., Conclusions and Relevance: In this study, otolaryngologists were significantly more likely than other specialists to perform a tracheotomy for patients with history of neck surgery, morbid obesity, and ongoing anticoagulation therapy. These findings suggest that patients undergoing tracheotomy performed by an otolaryngologist are more likely to present with complex and challenging clinical characteristics.

Objective: We aimed to discern clinico-demographic predictors of large (≥8) tracheostomy tube size placement, and, secondarily, to assess the effect of large tracheostomy tube size and other parameters on odds of decannulation before hospital discharge., Summary of Background Data: Factors determining choice of tracheostomy tube size are not well-characterized in the current literature, despite evidence linking large tracheostomy tube size with posttracheotomy tracheal stenosis. The effect of tracheostomy tube size on timing of decannulation is also unknown, an important consideration given reported associations between endotracheal tube size and probability of failed extubation., Methods: We collected information pertaining to patients who underwent tracheotomy at 1 of 10 U.S. health care institutions between 2010 and 2019. Tracheostomy tube size was dichotomized (≥8 and <8). Multivariable logistic regression models were fit to identify predictors of (1) large tracheostomy tube size, and (2) decannulation before hospital discharge., Results: The study included 5307 patients, including 2797 (52.7%) in the large tracheostomy cohort. Patient height (odds ratio [OR] = 1.060 per inch; 95% confidence interval [CI] 1.041-1.070) and obesity (1.37; 95% CI 1.1891.579) were associated with greater odds of large tracheostomy tube; otolaryngology performing the tracheotomy was associated with significantly lower odds of large tracheostomy tube (OR = 0.155; 95% CI 0.131-0.184). Large tracheostomy tube size (OR = 1.036; 95% CI 0.885-1.213) did not affect odds of decannulation., Conclusions: Obesity was linked with increased likelihood of large tracheostomy tube size, independent of patient height. Probability of decannulation before hospital discharge is influenced by multiple patient-centric factors, but not by size of tracheostomy tube., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To examine whether cochlear implantation (CI) increases the risk of clinically significant falls in older adults., Study Design: Retrospective analysis of deidentified administrative claims from a US commercial insurance database., Setting: Nationwide deidentified private insurance claims database (Clinformatics Data Mart; Optum)., Methods: Patients undergoing CI were identified through Current Procedural Terminology codes. Number of days with falls resulting in health care expenditure were counted 1 year pre- and post-CI. Generalized estimating equation Poisson regression was used to determine medical and sociodemographic predictors for fall days, including age, sex, race, and income, with pre- vs post-CI status., Results: Between 2003 and 2019, 3773 patients aged >50 years underwent CI. An overall 139 (3.68%) patients recorded at least 1 fall diagnosis a year pre-CI, and 142 (3.76%) recorded at least 1 fall diagnosis post-CI. The average number of days with fall diagnoses per patient with a recorded fall was 3.12 pre-CI and 2.04 post-CI. In bivariate analysis, age ( P < .0001) and Charlson Comorbidity Index ( P < .0001) were predictive of falls, but sex ( P < .10), race ( P < .72), and income ( P < .51) were not. Poisson regression demonstrated a statistically significant association between Charlson Comorbidity Index and days with fall diagnoses (risk ratio, 1.39 [95% CI, 1.30-1.49]; P < .0001]). No statistically significant difference in falls was seen pre- vs post-CI (risk ratio, 0.67 [95% CI, 0.34-1.33]; P < .25]). Age also was not predictive of falls in multivariate analysis., Conclusions: CI does not appear to increase the risk of falls in older adults. Patient comorbidities correlate most strongly with fall risk and should be considered in patient selection for CI.

Proliferation of pancreatic β-cells has long been known to reach its peak in the neonatal stages and decline during adulthood. However, β-cell proliferation has been studied under the assumption that all β-cells constitute a single, homogenous population. It is unknown whether a subpopulation of β-cells retains the capacity to proliferate at a higher rate and thus contributes disproportionately to the maintenance of mature β-cell mass in adults. We therefore assessed the proliferative capacity and turnover potential of virgin β-cells, a novel population of immature β-cells found at the islet periphery. We demonstrate that virgin β-cells can proliferate but do so at rates similar to those of mature β-cells from the same islet under normal and challenged conditions. Virgin β-cell proliferation rates also conform to the age-dependent decline previously reported for β-cells at large. We further show that virgin β-cells represent a long-lived, stable subpopulation of β-cells with low turnover into mature β-cells under healthy conditions. Our observations indicate that virgin β-cells at the islet periphery can divide but do not contribute disproportionately to the maintenance of adult β-cell mass., (© 2021 by the American Diabetes Association.)

Background: Septal extension grafts (SEGs) are used widely in rhinoplasty as a means of controlling tip position. Grafts positioned in a side-to-side configuration may cause nasal airway obstruction. Methods: Retrospective cohort analysis of patients undergoing cosmetic rhinoplasty. Patients undergoing SEG placement were grouped according to completion of the Nasal Obstruction Symptom Evaluation (NOSE) or Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS). The latter has a cosmetic (C) and functional (O) domain. Each group was matched to a cohort that did not undergo SEG placement using criteria: preoperative NOSE or SCHNOS-O score, age, and gender. Patient demographics and outcomes, including NOSE, SCHNOS, and visual analog scale (VAS) scores, were compared between SEG and no-SEG groups using univariate and multivariate analyses. If patients underwent placement of an SEG and complained of obstruction, the laterality of the graft in relation to the complaint was examined. Results: SEGs were placed in 79 patients, of whom 77 completed the NOSE survey and 37 completed the SCHNOS-O both pre- and postoperatively. These patients were matched to patients without SEGs. For both the SCHNOS and NOSE-matched cohorts, functional outcomes (NOSE, SCHNOS-O, and VAS-F) did not significantly differ between SEG and no-SEG groups. These findings were also observed when patients were stratified by cosmetic surgery alone versus combined functional and cosmetic surgery. On multivariate linear regression analysis, when accounting for intraoperative techniques, there was no difference in postoperative NOSE or SCHNOS-O outcomes between the SEG and no-SEG cohorts. Side of postoperative nasal obstruction did not correlate with side of SEG placement. Conclusion: SEGs, when used in a unilateral side-to-side configuration, yield excellent aesthetic results without compromising functional outcomes.

Background and Objectives: Anxiety disorders comprise the most common category of mental illness among US young adults. Art making might be one method to help reduce anxiety, but the few studies investigating this have used only subjective measures of anxiety., Design: This study employed both subjective (self-reported state anxiety from the State-Trait Anxiety Inventory) and objective (heart rate variability) measures to assess whether 30-minute periods of art making reduced anxiety in 47 first-year college students prior to their final examinations., Methods: Students participated in free-form painting, mandala coloring, clay modeling, and control sessions., Results: Repeated-measures ANOVA with post hoc analysis revealed significantly greater pre- to post-session reductions in anxiety for all three types of art-making sessions than for the control session, as measured objectively. Measured subjectively, only free-form painting yielded a significant decrease in anxiety compared to the control session., Conclusions: Given the health benefits of anxiety reduction, further study is warranted to determine the duration of art making's anxiety-reducing effect.

Cytochrome P450 2D7 (CYP2D7) has long been considered a pseudogene. A recent report described an indel polymorphism (CYP2D7 138delT) that causes a frameshift generating an open reading frame and functional protein. This polymorphism was observed in 6 of 12 samples from an Indian population. Individuals with the 138delT polymorphism expressed CYP2D7 protein from a brain-specific, alternatively spliced transcript (J Biol Chem 279:27383-27389, 2004). The unexpectedly high frequency of the variant allele and resulting CYP2D7 expression could have important implications for brain-specific metabolism of CYP2D substrates including many psychoactive drugs. However, the 138delT variant has not been detected in other studies (Pharmacogenetics 11:45-55, 2001; Biochem Biophys Res Commun 336:1241-1250, 2005). Our goal was to determine the frequency of this variant in a larger, ethnically diverse population. CYP2D7 138delT genotypes for 163 Caucasians, 95 East Asians, 50 Indians, 68 Hispanic Latinos, and 68 African Americans were determined by Pyrosequencing. The 138delT allele was observed at a frequency of 1.0% in East Asians and 0.74% in Hispanic Latinos. The deletion was not observed in Indians or the other ethnic populations. In addition, in each of the three samples with 138delT, the putative brain-specific transcript contains a premature stop codon that would preclude protein expression. The low frequency of the CYP2D7 138delT polymorphism in our ethnically diverse sample, and particularly the absence from 50 Indian samples, is in contrast to the high frequency previously reported. Our results suggest that CYP2D7 138delT is unlikely to be highly relevant for population variation of pharmacokinetics or drug response.

Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888., Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation., Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity., Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.

beta(2)-Adrenergic agonists are known to improve muscle strength because of anabolic properties. The purpose of this study was to determine if long-term administration of a long-acting beta(2)-adrenergic agonist to subjects with tetraplegia is associated with improvement in pulmonary function parameters and maximal static inspiratory and expiratory mouth pressures (MIP and MEP, respectively), measures of respiratory muscle strength. The study was a randomized, prospective, double-blind, placebo-controlled, crossover trial and conducted at the James J. Peters Veterans Affairs Medical Center. Thirteen subjects who had complete or incomplete tetraplegia for more than one year participated in the study. Eleven subjects completed the study. All were clinically stable outpatients without any history of asthma or use of inhaled bronchodilators. Following baseline measurements, patients were randomized to receive salmeterol or placebo from identically marked Diskus containers for 4 weeks. Following a 4-week washout period, the subjects were randomized to receive the alternate preparation for 4 weeks. Pulmonary function parameters and static mouth pressure were measured during baseline and during the fourth week of the two study periods. During the 4-week period of salmeterol administration, forced vital capacity, forced expiratory volume in 1 s, peak expiratory flow, MIP, and MEP improved significantly compared with placebo and baseline. Expiratory reserve volume increased significantly compared to baseline. Increases in MIP and MEP during salmeterol administration suggest improvement in respiratory muscle strength. However, this cannot be stated with certainty because MIP and MEP are dependent on volume parameters at which they are measured. Regardless of the mechanism, improvement in static mouth pressures indicates that salmeterol should benefit these individuals by improving cough effectiveness.

Objective: Our objective was to learn whether genetic polymorphisms of metabolic enzymes or transport proteins provide a mechanistic understanding of the in vivo disposition of atrasentan, a selective endothelin A receptor antagonist., Methods: Atrasentan uptake was measured in HeLa cells transfected to express major alleles of organic anion transporting polypeptide 1B1 (OATP1B1). The results were used to classify individuals as extensive, intermediate, or poor OATP1B1 transporters according to their SLCO1B1 genotypes. Analysis of covariance including genotype, study, age, weight, sex, and ethnicity was used to identify factors influencing atrasentan single-dose (n = 44) and steady-state (n = 38) pharmacokinetic parameters. Genotypes for cytochrome P450 3A5, uridine diphosphate-glucuronosyltransferase (UGT) 1A1, UGT2B4, UGT2B15, adenosine triphosphate-binding cassette subfamily B (ABCB) 1, solute carrier organic anion transporter (SLCO) 1B1, and solute carrier family 22 (SLC22) A2 were each assessed., Results: Single-dose atrasentan exposure (P = .0244), steady-state atrasentan exposure (P = .0108), and maximum postdose plasma concentration (P = .0002) were associated with OATP1B1 activity classified by SLCO1B1 genotype. No other tested genotypes were observed to be associated with both single-dose and steady-state atrasentan pharmacokinetics., Conclusions: OATP1B1 is a meaningful factor for atrasentan disposition. Individuals may be classified as having extensive, intermediate, or poor OATP1B1 transport phenotypes according to SLCO1B1 genotypes. Increased exposures of OATP1B1 substrates might be expected in individuals who have the poor transporter phenotype or are treated with an OATP1B1 inhibitor.

Purpose: ABT-751 is an oral antimitotic agent that binds to the colchicine site on beta-tubulin. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of ABT-751 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias., Study Design: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m(2) (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m(2) (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC)., Results: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m(2), with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala(185)Thr, was identified in exon 4 of the beta-tubulin gene, TUBB, in three other patients. The recommended phase 2 dose in hematologic malignancies is 175 mg/m(2) daily orally for 21 days every 4 weeks., Conclusion: Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.

Study Objectives: Previous spirometric findings among subjects with chronic tetraplegia that reduction in FEV1 and maximal forced expiratory flow, mid-expiratory phase (FEF(25-75%)) correlated with airway hyperresponsiveness to histamine, and that many of these subjects exhibited significant bronchodilator responsiveness, suggested that baseline airway caliber was low in this population. To better evaluate airway dynamics in patients with spinal cord injury, we used body plethysmography to determine specific airway conductance (sGaw), a less effort-dependent and more reflective surrogate marker of airway caliber., Design: Cohort study., Setting: Veterans Affairs medical center., Participants: Thirty clinically stable subjects with chronic spinal cord injury, including 15 subjects with tetraplegia (injury at C4-C7) and 15 subjects with low paraplegia (injury below T7), participated in the study. Fifteen able-bodied individuals served as a control group., Interventions: Subjects underwent baseline assessment of spirometric and body plethysmographic parameters. Repeat measurements were performed among subjects with tetraplegia and paraplegia before and 30 min after receiving aerosolized ipratropium bromide (2.5 mL 0.02% solution; 12 subjects) or normal saline solution (2.5 mL; 6 subjects)., Measurements and Results: We found that subjects with tetraplegia had significantly reduced mean values for sGaw (0.16 cm H2O/s), total lung capacity, FVC, FEV1, and FEF(25-75%) compared to subjects in the other two groups. Subjects with tetraplegia who received ipratropium bromide experienced significant increases in sGaw (135%), FEV1 (12%; 260 mL), and FEF(25-75%) (27%). Significant, though far smaller, increases in sGaw (19%) were found among subjects with paraplegia. No discernable change in any pulmonary function parameter was found following the administration of normal saline solution., Conclusions: Subjects with tetraplegia, as opposed to those with low paraplegia, have reduced baseline airway caliber due to heightened vagomotor airway tone, which we hypothesize is the result of the interruption of sympathetic innervation to the lungs, and/or from low circulating epinephrine levels.

Objective: To determine differences in peripheral and cardiovascular autonomic function between individuals with acute musculoskeletal injury (<1 week) and healthy controls., Methods: Autonomic cardiovascular modulation, baroreceptor sensitivity, skin conductance, and peripheral skin temperature were obtained in 6 subjects with acute musculoskeletal injury and 6 age- and sex-matched controls. Power spectral analysis was performed on both beat-to-beat R-R intervals and continuous systolic blood pressure (SBP) peaks. Baroreceptor sensitivity was derived using both heart rate and blood pressure spectral analysis components., Results: The SD of R-R intervals was significantly different for the acute injury group relative to controls (49.8 +/- 10.5 vs 76.8 +/- 12.7 ms; P < .01). Continuous SBP peaks and skin conductance (sympathetic vasomotor and sudomotor indices, respectively) were significantly higher (59.6 +/- 6.7 vs 23.8 +/- 6.4 mm Hg2 /Hz, and 3.87 +/- 1.04 vs 2.19 +/- 0.3 mhos; P < .01, respectively) and baroreceptor sensitivity lower (0.97 +/- 0.07 vs 1.10 +/- 0.08 mm Hg; P < .02) in the acute injury group compared with controls. Regression analysis revealed a significant relationship between skin conductance and continuous SBP peaks (r = 0.75; P < .01)., Conclusions: These findings suggest that interaction between cutaneous and vasomotor sympathetic neurons in response to acute musculoskeletal injury, reflected as increased afferent input from sensitized nociceptors and other sensory neurons, results in alterations in autonomic function.

Background: The metabolizing enzyme cytochrome P450 (CYP) 3A5 is polymorphically expressed as a result of genetic variants that do not encode functional protein. Because of overlapping substrate specificity with CYP3A4 and the multidrug efflux pump P-glycoprotein, the importance of CYP3A5 genetic polymorphism for pharmacokinetics is controversial., Objective: Our objective was to determine whether genetic polymorphisms in CYP3A5 or MDR-1 (which encodes P-glycoprotein) influence the drug levels of ABT-773, a ketolide antibiotic that is a substrate for both CYP3A and P-glycoprotein., Methods: Healthy volunteers given 3 different oral dose levels of ABT-773 were genotyped at 2 common CYP3A5 and 7 common MDR-1 polymorphisms. Individuals were categorized as CYP3A5-positive if they carried at least 1 functional CYP3A5*1 allele and as CYP3A5-negative if they did not. Area under the plasma concentration-time curves (AUCs) from 0 to 6 hours (AUC(t)) and maximum postdose plasma concentration (C(max)) after a single dose and on day 5 of a twice-daily regimen were calculated and correlated with genotypes., Results: ABT-773 AUC(t) and C(max) were, on average, higher in CYP3A5-negative subjects given 450 mg ABT-773 (n = 9) than in CYP3A5-positive subjects with identical doses (n = 8). The relationship for AUC(t) was statistically significant both after a single dose (geometric mean and 95% confidence interval [CI], 5.0 microg.h/mL [3.9-6.4 microg.h/mL] versus 2.8 microg.h/mL [1.8-4.3 microg.h/mL]; P =.03) and on the fifth day of twice-daily dosing (12.4 microg.h/mL [8.7-17.6 microg.h/mL] versus 7.4 microg.h/mL [5.5-9.8 microg.h/mL], P =.04). The relationship for C(max) was statistically significant after a single dose (1220 microg/mL [867-1167 microg/mL] versus 727 microg/mL [506-1044 microg/mL], P =.04) and showed a trend in the same direction on the fifth day of twice-daily dosing (2566 microg/mL [1813-3631 microg/mL] versus 1621 microg/mL [1122-2343 microg/mL], P =.07). In contrast, AUC(t) and C(max) were not significantly different between CYP3A5-positive and CYP3A5-negative individuals given 150 mg or 300 mg ABT-773. ABT-773 plasma levels did not trend with MDR-1 genotypes., Conclusions: These results suggest that CYP3A5 genotype may be an important determinant of in vivo drug disposition and that this effect may be dose-dependent.

This study utilized cytochrome P450 2D6 (CYP2D6) genotypes to explain variability of desipramine pharmacokinetics in a cohort of non-poor metabolizer individuals. In an interaction study utilizing desipramine as a probe, genotyping for the CYP2D6*3, *4, *5 and *6 alleles was used to screen out CYP2D6 poor metabolizers. Individuals were categorized according to these and additional alleles (CYP2D6*2, *9, *10, *17, *41 and x2). Genotypes of individuals heterozygous for two or three of *2, *17 and *41 alleles were confirmed by molecular haplotyping. Pharmacokinetic parameters of desipramine were analysed according to CYP2D6 category. Molecular haplotyping was necessary to definitively categorize four of 16 individuals. A subject who had unusually high plasma elimination half-time, exposure and metabolic ratios carried an intermediate metabolizer (IM) *9 allele in combination with a non-functional allele. This combination has a population frequency of less than 1 : 200. Individuals with *1/*1, *1/*2 and *2/*2 genotypes had lower than average plasma elimination half-time, exposure and metabolic ratios. For desipramine, additional genotyping of CYP2D6 IM alleles helped define subgroups of the CYP2D6-positive cohort. This suggests that genotyping for IM alleles will aid in interpretation of clinical trials involving CYP2D6 substrates. Due to the diversity of IM alleles, molecular haplotyping may be necessary to fully characterize CYP2D6 genotype-phenotype relationships., (Copyright 2004 Lippincott Williams & Wilkins)

Single-nucleotide polymorphisms (SNPs) provide an abundant source of DNA polymorphisms in a number of eukaryotic species. Information on the frequency, nature, and distribution of SNPs in plant genomes is limited. Thus, our objectives were (1) to determine SNP frequency in coding and noncoding soybean (Glycine max L. Merr.) DNA sequence amplified from genomic DNA using PCR primers designed to complete genes, cDNAs, and random genomic sequence; (2) to characterize haplotype variation in these sequences; and (3) to provide initial estimates of linkage disequilibrium (LD) in soybean. Approximately 28.7 kbp of coding sequence, 37.9 kbp of noncoding perigenic DNA, and 9.7 kbp of random noncoding genomic DNA were sequenced in each of 25 diverse soybean genotypes. Over the >76 kbp, mean nucleotide diversity expressed as Watterson's theta was 0.00097. Nucleotide diversity was 0.00053 and 0.00111 in coding and in noncoding perigenic DNA, respectively, lower than estimates in the autogamous model species Arabidopsis thaliana. Haplotype analysis of SNP-containing fragments revealed a deficiency of haplotypes vs. the number that would be anticipated at linkage equilibrium. In 49 fragments with three or more SNPs, five haplotypes were present in one fragment while four or less were present in the remaining 48, thereby supporting the suggestion of relatively limited genetic variation in cultivated soybean. Squared allele-frequency correlations (r(2)) among haplotypes at 54 loci with two or more SNPs indicated low genome-wide LD. The low level of LD and the limited haplotype diversity suggested that the genome of any given soybean accession is a mosaic of three or four haplotypes. To facilitate SNP discovery and the development of a transcript map, subsets of four to six diverse genotypes, whose sequence analysis would permit the discovery of at least 75% of all SNPs present in the 25 genotypes as well as 90% of the common (frequency >0.10) SNPs, were identified.

Objective: The relationship of respiratory symptoms to pulmonary function parameters and smoking status was assessed in subjects with chronic (>1 year) spinal cord injury (SCI)., Methods and Participants: As part of their annual physical examination, subjects were queried regarding respiratory symptoms and underwent pulmonary function studies. The 180 patients who successfully completed pulmonary function testing were evaluated, including 79 subjects with tetraplegia (56 nonsmokers and 23 smokers) and 101 subjects with paraplegia (78 nonsmokers and 23 smokers)., Findings: Logistic-regression analysis revealed the following independent predictors of breathlessness: level of injury (tetraplegia, paraplegia, odds ratio = 3.5, P < 0.0015), cough combined with phlegm and/or wheeze (CPWZ, odds ratio = 3.1, P < 0.015), total lung capacity percentage predicted (TLC <60%, odds ratio = 3.9, P < 0.02), and expiratory reserve volume (ERV < 0.6 L, odds ratio = 2.5, P < 0.05). Independent predictors of CPWZ were current smoking (odds ratio = 3.3, P < 0.004), breathlessness (odds ratio = 2.9, P < 0.03), and forced expiratory volume in 1 second (FEV1 <60%, odds ratio = 3.2, P < 0.01)., Conclusion: Altered respiratory mechanics associated with tetraplegia contribute to breathlessness, restrictive ventilatory impairment (low TLC%), and reduced expiratory muscle strength (low ERV). These factors apparently overshadow adverse effects caused by smoking. Conversely, smoking and reduction of airflow (low FEV1%) were predictive of CPWZ, symptoms commonly associated with cigarette use.

The effects of autonomic dysfunction and regular activity on the cardiovascular system were investigated. The 48 participants included 12 subjects with tetraplegia, 12 subjects with paraplegia, 12 sedentary subjects, and 12 endurance-trained able-bodied controls. Central and peripheral autonomic data were obtained at rest to estimate efferent cardiac vagal output and sympathetic vasomotor control, and plasma norepinephrine concentration was determined as a marker of peripheral sympathetic activity. Cardiovascular parameters were obtained using a noninvasive cardiac output maneuver. The group with paraplegia did not differ from the sedentary group for efferent cardiac vagal output, but all other group comparisons were different (p <0.05). Sympathetic vasomotor control and stroke index were also similar between the paraplegia and sedentary groups, whereas both were increased in the endurance-trained group and were significantly reduced in the tetraplegia group. A strong relation between efferent cardiac vagal output and stroke index was established for the total group (r = 0.78, p <0.01), and analysis of covariance determined that the slope of this relation was similar among the groups. Sympathetic vasomotor control correlated significantly with plasma norepinephrine (r = 0.57, p <0.01), and a relation between sympathetic vasomotor control and stroke index was identified for the total group (r = 0.40, p <0.01). These results suggest that vagal control of resting central cardiac function is maintained despite autonomic dysfunction. The comparable findings in the paraplegia and sedentary groups suggest that regardless of peripheral autonomic dysfunction, the absence of regular physical activity has a similar effect on the resting vagal modulation and stroke index.

Factor V is a plasma protein essential for blood coagulation. This protein is involved in activated protein C resistance, the most common inherited thrombotic disorder known. We utilized the polymerase chain reaction to clone the porcine factor V gene by generating overlapping clones amplified with primers chosen by comparison with known nucleotide sequences. The porcine factor V cDNA contig encodes a predicted 2258-amino acid protein, making it the largest in comparison to the bovine, human, and murine proteins. Porcine factor V has the highest level of homology with bovine factor V, but also has high levels of conservation of important residues with all the species. Radiation hybrid mapping assigned the porcine factor V gene to chromosome 4. Three-dimensional models of factor V were generated and used to analyze membrane-binding sites in terms of conserved, and therefore likely important residues.

Objectives: We administered aerosolized histamine to 32 subjects with tetraplegia to determine whether there were differences in spirometric and/or lung volume parameters between responders and nonresponders., Results: Baseline pulmonary function parameters revealed mild to moderate restrictive dysfunction. We found that 25 subjects (78%) were hyperreactive to histamine (mean provocative concentration of a substance causing a 20% fall in FEV(1) [PC(20)], 1.77 mg/mL). Responders (PC(20), < 8 mg/mL) had significantly lower values for forced expiratory flow between 25% and 75% of the outflow curve (FEF(25-75)), FEF(25-75) percent predicted, and FEF(25-75)/FVC ratio. Among all 32 subjects, the natural logarithmic transformation performed on PC(20) values (lnPC(20)) correlated with FEF(25-75) percent predicted, FEV(1) percent predicted, and FEF(25-75)/FVC ratio but not with FVC percent predicted. Responders with PC(20) values < 2 mg/mL (n = 13) had significantly reduced values for FVC, FVC percent predicted, FEV(1), and FEV(1) percent predicted compared to those with PC(20) values between 2 mg/mL and 8 mg/mL. In addition, among responders, there was a significant correlation between lnPC(20) and FVC percent predicted. A significant relationship was found between maximal inspiratory pressure (PImax) and both FEV(1) percent predicted and FEF(25-75) percent predicted, but not between lnPC(20) and either PImax or maximal expiratory pressure (PEmax)., Conclusions: These findings demonstrate that subjects with tetraplegia who exhibit airway hyperreactivity (AHR) have reduced baseline airway caliber and that lower values for lnPC(20) are associated with parallel reductions in surrogate spirometric indexes of airway size (FEV(1) percent predicted and FEF(25-75) percent predicted) and airway size relative to lung size (FEF(25-75)/FVC ratio). The absence of an association between lnPC(20) and FVC percent predicted for the entire group or between lnPC(20) and either PImax or PEmax indicates that reduced lung volumes secondary to respiratory muscle weakness cannot explain the mechanism(s) underlying AHR. Among responders, however, a possible role for reduction in lung volume, as it pertains to increasing AHR, cannot be excluded. Proposed mechanisms for reduced baseline airway caliber relative to lung size in subjects with tetraplegia include unopposed parasympathetic activity secondary to the loss of sympathetic innervation to the lungs and/or the inability to stretch airway smooth muscle with deep inhalation.

Objective: To determine the effect of the GABA-agonist baclofen on cough reflex sensitivity in subjects with cervical spinal cord injury (C-SCI). Baclofen has been shown to inhibit the cough reflex in able-bodied volunteers., Design: Prospective, nonrandomized control trial., Setting: Veterans Affairs medical center with large outpatient SCI population., Participants: Twelve adult males (11 outpatients) with C-SCI chronically maintained on oral baclofen for the treatment of muscle spasm., Intervention: Subjects underwent cough challenge testing with inhaled capsaicin. The concentrations (microM) of capsaicin inducing 2 or more (C2) and 5 or more (C5) coughs were determined. Mean values for log C2 and log C5 were compared with a control group of outpatients with C-SCI not receiving baclofen., Results: Subjects treated with baclofen had a significantly higher cough threshold (diminished cough reflex sensitivity) than control subjects. Mean (+/- standard error of the mean) values for log C2 in study subjects and controls were 1.28 +/- .16 and .65 +/- .15, respectively (p = .009). Mean values for log C5 in subjects receiving baclofen and in control subjects were 2.20 +/- .22 and 1.43 +/- .23, respectively (p = .024). Subjects and controls did not differ in terms of age, spirometric parameters, or duration of injury., Conclusions: The results suggest that chronic therapy with baclofen diminishes cough reflex sensitivity in subjects with C-SCI. The clinical significance of this finding remains to be elucidated.

The effects of autonomic disruption and inactivity were studied on the venous vascular system. Forty-eight subjects, 24 with spinal cord injury (SCI) and 12 sedentary and 12 active able-bodied controls, participated in this study. Peripheral autonomic data were obtained to estimate sympathetic vasomotor control [low-frequency component of systolic blood pressure (LF(SBP))]. Vascular parameters were determined using strain-gauge venous occlusion plethysmography: venous capacitance (VC), venous emptying rate (VER), and total venous outflow (VO(t)). An additional vascular parameter was calculated: venous compliance [(VC/occlusion pressure) x 100]. VC and VO(t) were significantly different (SCI < sedentary < active). VER adjusted for VC was not different for any group comparison, whereas venous compliance was significantly lower in the SCI group than in the able-bodied groups and in the sedentary group compared with the active group. Regression analysis for the total group revealed a significant relationship between LF(SBP) and venous compliance (r = 0.64, P < 0.0001). After controlling for LF(SBP) through analysis of covariance, we found that mean differences for all venous vascular parameters did not change from unadjusted mean values. Our findings suggest that in subjects with SCI, the loss of sympathetic vasomotor tone contributes more than inactivity to reductions in venous vascular function. Heightened VC, VO(t), vasomotor tone, and venous compliance in the active group compared with the sedentary group imply that regular endurance training contributes to optimal venous vascular function and peripheral autonomic integrity.

Cartilage is a tissue that is primarily extracellular matrix, the bulk of which consists of proteoglycan aggregates constrained within a collagen framework. Candidate components that organize the extracellular assembly of the matrix consist of collagens, proteoglycans and multimeric glycoproteins. We describe the human gene structure of a potential organizing factor, a cartilage-derived member of the C-type lectin superfamily (CLECSF1; C-type lectin superfamily) related to the serum protein, tetranectin. We show by Northern analysis that this protein is restricted to cartilage and locate the gene on chromosome 16q23. We have characterized 10.9 kb of sequence upstream of the first exon. Similarly to human tetranectin, there are three exons. The residues that are conserved between CLECSF1 and tetranectin suggest that the cartilage-derived protein forms a trimeric structure similar to that of tetranectin, with three N-terminal alpha-helical domains aggregating through hydrophobic faces. The globular, C-terminal domain that has been shown to bind carbohydrate in some members of the family and plasminogen in tetranectin, is likely to have a similar overall structure to that of tetranectin.

To develop additional microsatellite (MS) markers in the region of the porcine skeletal muscle ryanodine receptor gene (RYR1), a microdissected genomic library was generated from the proximal half of the q arm of swine chromosome 6. Purified DNA was restriction enzyme-digested, ligated to oligonucleotide adaptors and amplified by PCR using primers complementary to the adaptor sequences. The purity of the amplified products and boundaries of the microdissected chromosomal region were verified by fluorescence in situ hybridization. (CA)n-containing sequences were then identified in a small insert genomic library generated from the PCR-amplified microdissected DNA. Oligonucleotide primers were developed for the PCR amplification of 30 of the 46 (CA)n repeat-containing clones, which were subsequently used to amplify DNA isolated from unrelated pigs of different breeds to determine the informativeness of these MS markers. Twenty-two of these MS markers were genotyped on the University of Illinois Yorkshire x Meishan swine reference population. These 22 markers were all assigned within a 50.7-CM region of the swine chromosome 6 linkage map, indicating the specificity of the microdissected library.

Study Objective: Aerosolized ipratropium bromide or orally administered baclofen or oxybutynin chloride (Ditropan) block methacholine-associated airway hyperreactivity in subjects with chronic cervical spinal cord injury (SCI), whereas these agents do not inhibit airway hyperreactivity associated with the inhalation of histamine. The present study was performed to determine whether pretreatment with a beta2-agonist attenuates airway hyperresponsiveness in these subjects., Participants: Subjects with chronic cervical SCI previously demonstrating airway hyperreactivity were challenged with methacholine (n = 9) or histamine (n = 16) alone and, on a separate day, 25 min following inhalation of nebulized metaproterenol sulfate., Results: Inhalation of the beta2-agonist was associated with an increase in provocative concentration causing a 20% decrease in FEV1 (PC20) values (geometric mean) from 1.01+/-2.76 to 20.54+/-6.24 mg/mL for methacholine and from 2.29+/-2.26 to 19.82+/-5.93 mg/mL for histamine. No correlation was found between specific PC20 values for individual subjects and percentage improvement in FEV1 (liter) following inhalation of metaproterenol sulfate and between PC20 values and baseline FEV1 percent., Conclusion: These data, combined with findings that patients with chronic high cervical SCI experience increased breathlessness following exposure to exogenous agents, suggest that long-term prophylactic beta2-agonist therapy may reduce respiratory symptoms associated with airway hyperreactivity in these patients.

Background: Pulmonary complications are a major cause of morbidity and mortality among individuals with cervical spinal cord lesions. Strengthening of the respiratory musculature may reduce these complications. Anabolic steroids have been used to increase muscle mass and improve muscle performance. Oxandrolone, an anabolic steroid, may have beneficial effects on breathing in persons with tetraplegia., Methods: The effect of one-month treatment with oxandrolone on weight gain and pulmonary function was studied in ten subjects with complete motor tetraplegia. Spirometry, maximal inspiratory and expiratory pressures, and resting self-rating of dyspnea (Borg Scale) were measured at baseline and repeated again at the end of one month of oxandrolone therapy (20 mg/day). Serum lipid profiles and liver function tests were performed before and after treatment. A paired t-test was used to determine pre- and post-treatment differences on the dependent variables. Percent change from baseline was calculated for each variable and tested using a one-sample t-test., Results: On average, the subjects gained 1.4+/-1.5 kg, a 2+/-2% increase in weight (p=0.01). A significant, 9+/-2% improvement was found in the combined measures of spirometry (p<0.005). Maximal inspiratory pressure improved an average of 10+/-7% (p<0.001). Maximal expiratory pressure improved 9+/-13% (non-significant). Subjective self-rating of dyspnea decreased an average of 37+/-28% (p<0.01)., Conclusions: In healthy subjects with tetraplegia, the use of oxandrolone was associated with significant improvements in weight and pulmonary function, and a subjective reduction in breathlessness. Therefore, oxandrolone may be indicated to strengthen respiratory musculature in individuals who have tetraplegia and ventilatory insufficiency aggravated by superimposition of pneumonia or other such conditions. However, long-term use of oxandrolone may not be indicated, due to the adverse complications associated with this class of agents.

An effective cough requires an intact cough reflex as well as adequate respiratory muscle function to generate elevated intrathoracic pressures. Since the major muscles of expiration are innervated by the first thoracic segment and below, transection of the cervical spinal cord results in severely compromised expiratory function and cough. To investigate the effects of cervical spinal cord injury (C-SCI) on cough reflex sensitivity, we measured responsiveness to inhaled capsaicin in 12 male subjects with chronic C-SCI and compared findings to those from a control group of 50 able-bodied men. The concentrations (microM) of capsaicin inducing two or more (C2) and five or more coughs (C5) did not significantly differ between the two groups. Mean (+/- SEM) values for log C2 in subjects with C-SCI and control subjects were 0.65 +/- 0.15 and 0.87 +/- 0.07, respectively (p = 0.15). Mean values for log C5 in subjects with C-SCI and control subjects were 1.43 +/- 0.23 and 1.41 +/- 0.08, respectively (p = 0.94). We conclude that cough reflex sensitivity is preserved after C-SCI, and that ineffective cough in this population results primarily from the loss of innervation of respiratory muscles.

The majority of otherwise healthy subjects with chronic cervical spinal cord injury (SCI) demonstrate airway hyperresponsiveness to aerosolized methacholine or histamine. The present study was performed to determine whether ultrasonically nebulized distilled water (UNDW) induces airway hyperresponsiveness and to further elucidate potential mechanisms in this population. Fifteen subjects with SCI, nine with tetraplegia (C4-7) and six with paraplegia (T9-L1), were initially exposed to UNDW for 30 s; spirometry was performed immediately and again 2 min after exposure. The challenge continued by progressively increasing exposure time until the forced expiratory volume in 1 s decreased 20% or more from baseline (PD20) or the maximal exposure time was reached. Five subjects responding to UNDW returned for a second challenge 30 min after inhalation of aerosolized ipratropium bromide (2.5 ml of a 0.6% solution). Eight of nine subjects with tetraplegia had significant bronchoconstrictor responses to UNDW (geometric mean PD20 = 7.76 +/- 7.67 ml), whereas none with paraplegia demonstrated a response (geometric mean PD20 = 24 ml). Five of the subjects with tetraplegia who initially responded to distilled water (geometric mean PD20 = 5.99 +/- 4.47 ml) were not responsive after pretreatment with ipratropium bromide (geometric mean PD20 = 24 ml). Findings that subjects with tetraplegia are hyperreactive to UNDW, a physicochemical agent, combined with previous observations of hyperreactivity to methacholine and histamine, suggest that overall airway hyperresponsiveness in these individuals is a nonspecific phenomenon similar to that observed in patients with asthma. The ability of ipratropium bromide to completely block UNDW-induced bronchoconstriction suggests that, in part, airway hyperresponsiveness in subjects with tetraplegia represents unopposed parasympathetic activity.

Due to the increased prevalence of ischemic heart disease and hypertension reported in individuals with chronic spinal cord injury (SCI), we investigated whether subjects with low level SCI (paraplegia), without apparent evidence of coronary artery disease, exhibit normal baroreceptor and autonomic function. Eighteen males participated in this study: seven normotensive with paraplegia, five hypertensive with paraplegia and six normotensive non-SCI controls. The Valsalva maneuver was performed by maintaining a pressure of 40 mmHg over 15 s and R-R intervals (RRI) and arterial blood pressure were measured continuously. Phase IV of the Valsalva maneuver was determined by linear regression analysis between RRI and systolic pressure, with a final slope calculated. The power spectra for RRI and blood pressure variability parameters were also analyzed, in addition to the index alpha, a frequency domain estimate of the overall gain in baroreceptor control of the RRI-arterial blood pressure. The normotensive subjects with paraplegia were found to have an impaired baroreceptor response when compared with age-matched, non-SCI controls. In addition, the levels of both the low frequency and high frequency spectral components of RRI and the index alpha were reduced in these individuals at rest. These cumulative findings strongly suggest that the integrity of the sinoaortic baroreceptors, as well as efferent parasympathetic function, may be compromised in otherwise apparently healthy individuals with chronic paraplegia.

Objective: To determine whether pulmonary function, respiratory muscle strength, and dyspnea can be improved in individuals with chronic cervical spinal cord injury (SCI)., Study Design: Ten subjects participated in an 8-week resistive inspiratory muscle training (IMT) program for 15 minutes twice daily. Spirometry, lung volumes, maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and dyspnea were measured at baseline, week 4, and week 8. Six months after the study, spirometry, MIP, and MEP were re-measured in a subgroup of the original participants., Results: We found that regular IMT in subjects with cervical SCI significantly improved forced vital capacity (means +/- SE) (11% +/- 2.82% increase), forced inspiratory vital capacity (21% +/- 6.91%), vital capacity (8% +/- 4.36%), total lung capacity (12% +/- 3.23%), functional residual capacity (15% +/- 5.96%), and MIP (24% +/- 6.98%) (p < .05). Furthermore, although no statistical differences were observed for the dyspnea scale, the fact that subjects reported decreased levels (43% +/- 21.30% reduction) of perceived difficulty breathing may be of greater importance. No significant differences from baseline values were found in the seven subjects whose spirometry and respiratory muscle strength were measured 6 months after the study., Conclusions: Our findings suggest that in individuals with cervical SCI regular resistive IMT may result in decreased restrictive ventilatory impairment and reported dyspnea and, thus, reduced incidence of chronic respiratory complaints, respiratory infection, and other pulmonary complications.