Tiotropium for the Treatment of Asthma: Patient Selection and Perspectives.

Asthma is a chronic disease of airway inflammation with a large global burden. Despite established, guideline-based stepwise therapy, a significant proportion of patients remain symptomatic and poorly controlled. As such, there is a need for additional safe, effective, convenient, and cost-effective therapies that can be broadly applied across a range of asthma phenotypes. Tiotropium is a long-acting muscarinic antagonist (LAMA) that leads to bronchodilation by blocking endogenous acetylcholine receptors in the airways. Tiotropium has long been approved for the treatment of chronic obstructive pulmonary disease, and it has recently been recognized for its safety and efficacy in improving lung function and controlling asthma. Evidence from several Phase III trials in the adult and paediatric population has shown that tiotropium is well tolerated and significantly improves a range of endpoints as an add-on treatment to ICS therapy, regardless of baseline characteristics and clinical phenotypes. Consequently, regulatory authorities worldwide have recently licensed tiotropium as the only LAMA approved for the treatment of asthma. This review provides an overview of safety and efficacy data and discusses the use of tiotropium in patients across the range of asthma severities, ages, and phenotypes.

Stroke rehabilitation: availability of a family member as caregiver and discharge destination.

BACKGROUND: In today's health care environment where resources are scarce discharge planning is an important component of resource allocation. Knowledge of the factors that influence discharge disposition is fundamental to such planning. Further, return to home is an important outcome metric related to the effectiveness of a stroke rehabilitation program. AIM: To test the hypothesis that the patients who have a caregiver at home willing to participate in the care of the patient discharged from a stroke rehabilitation unit are more likely to be discharged home given other predictive factors being the same. DESIGN: Retrospective cohort study using binary logistic regression analysis with outcome as discharge home vs. discharge not home after in-patient stroke rehabilitation. SETTING: Hamilton Health Sciences multidisciplinary integrated stroke program unit. POPULATION: During this period, 276 patients were admitted to the integrated stroke unit, of which 268 patients were living in the community prior to hospitalization. The remaining eight patients were admitted from a care facility, such as a nursing home or assisted living facility. Since a sample size of eight is too small, these patients were excluded from the analysis. As such, the analysis is based on the 268 patients who were living at home prior to the onset of stroke. METHODS: The data points collected during the study period were age, gender, days from stroke onset to rehabilitation unit admission, pre-stroke living arrangement (lived alone vs. lived with spouse, partner, or another family member), FIMTM at admission, type of stroke, laterality of impairment, and discharge destination (i.e., private dwelling vs. nursing home, assisted living facility, or back to acute care). RESULTS: As established by a number of previous studies, the most significant predictors of home as discharge destination was admission FIMTM. However, the second most important predictive factor for home discharge was prestroke living arrangement (lived alone vs lived with spouse/partner/other family member) as hypothesized by the authors. CONCLUSION: Literature is rich with studies showing functional independence to be the most important predictor of home as discharge disposition but our analysis shows that pre-stroke living arrangement, i.e., lived alone vs lived not alone is also an important predictor for patients to be discharged home after stroke rehabilitation. CLINICAL REHABILITATION IMPACT: If current discharge planning relies on the availability of a caregiver at home after discharge from in-patient stroke rehabilitation then it may be worthwhile to include these caregivers in the inpatient rehabilitation process, to prepare them for their loved one's return home. Additionally, once the patient is discharged home more resources should be made available to support caregivers in the community. This may include more home healthcare personnel training and availability along with respite care.

Lung epithelial permeability and inhaled furosemide: added dimensions in asthmatics.

OBJECTIVE: Lung clearance rates of inhaled (99m)Tc-DTPA aerosols constitute a sensitive index to evaluate the permeability changes characteristic of airway epithelial damage. It was thought that edema of the airway wall which is reported in asthma could be relieved with a diuretic like furosemide, helping to relieve the symptoms. We intended to study the effect of inhaled furosemide on lung epithelial permeability in asthmatics and smokers with the help of (99m)Tc-DTPA lung clearance test (LCT). METHODS: The study included three groups (n = 15), viz. normal healthy controls, asymptomatic chronic smokers, and chronic persistent asthmatics. Each subject underwent the LCT twice, baseline and post-furosemide (Lasix) study, within a week's interval. The post-furosemide study was carried out 15 min after inhalation of 10 mg of lasix. Lung epithelial permeability was determined in terms of clearance half-life (T (1/2)). RESULTS: The baseline mean T (1/2) values for controls, smokers, and asthmatics were 50.95 +/- 16.58, 20.81 +/- 5.47, 24.06 +/- 6.19 min, respectively. Post-lasix T (1/2) values were 50.83 +/- 15.84, 20.70 +/- 5.65, 41.27 +/- 15.07 min, respectively. There was a significant difference (P < 0.001) in baseline and post-lasix clearance values in asthmatics only. CONCLUSION: Baseline lung epithelial permeability was altered in smokers and asthmatics compared to the controls. Furosemide was effective only in asthmatics in reverting the permeability almost back to the normal range. Inhaled furosemide was effective even in moderate and severe asthmatics. Furosemide has multiple mechanisms of action. It possibly acts at bronchial level in view of the pathology in asthmatics lying in the airways.

UV-B Induced stimulation of phosphatidylinositol 3-kinase in human fetal hepatocytes.

We investigated the effect of UV-B irradiation on PI 3-kinase activity in human fetal hepatocytes. When cells were exposed to monochromatic (304nm) UV-B light, a significant increase in intracellular PI 3-kinase activity was observed in a dose dependent manner with maximal activity upon 1500 Jm(-2) irradiation. At 1500 Jm(-2) dose PI 3-kinse activity increased by 80% in membrane fraction of fetal hepatocytes of 25 weeks gestation. PI 3-kinse inhibitors wortmannin and LY294002 specifically inhibited the UV-B induced lipid kinase activity and blocked significantly the UV-B induced cell viability. The data suggests a correlation between cell survival and elevated levels of PI 3-kinase and suggest that UV-B irradiation at a dose of 1500 Jm(-2) is ideal for fetal hepatocyte transplantation. Also, PI 3-kinase levels could be a representative marker for viable UV-B irradiated fetal hepatocytes for transplantation.

The laparoscopic experience of surgical graduates in the United States.

BACKGROUND: Although laparoscopic surgery has become widespread during the past decade, no systematic study of the training needs exists. To obtain guidance for planning, we analyzed the national resident operative experience during the past 8 years. METHODS: The laparoscopic experiences of all surgical residents graduating between 1994 and 2001 were subjected to regression analysis. The laparoscopic volume of each trainee and change in ratio of laparoscopic/open operation over time were used to estimate the growth of individual laparoscopic operations in training programs. RESULTS: Laparoscopic surgery constituted only 5.7% of a trainee's total surgical experience in 1994, but comprised 13% by 2001. A resident completing training in 1994 performed 53 laparoscopic operations, of which 79% (42) were cholecystectomies. By 2001, a graduate performed 126 laparoscopic operations, of which 68% (86) were cholecystectomies. During the interim, most laparoscopic operations exhibited growth. Trainee experience in some newer operations has also increased steadily but at a much slower rate. CONCLUSIONS: This descriptive statistical survey of training experience yields a comprehensive picture of the laparoscopic capability of the young surgeon. The growth potential of some newer operations has also been measured. Using these data, guidelines can be drawn as to which operation programs should focus resources on training residents. Since competence depends on exposure, residency training alone may not provide sufficient depth to allow recent graduates to perform the newer operations independently.

The decline of training in open biliary surgery: effect on the residents' attitude toward bile duct surgery.

BACKGROUND: After more than a decade of growth for laparoscopic cholecystectomy and decline in open cholecystectomy, the impact on the training of resident's in other open biliary operations can be analyzed quantitatively. METHODS: The national operative statistics for residents' operations from 1988 to 2001 (data in the public domain) were analyzed by regression analysis to establish trends and to calculate the rate of change. For laparoscopic biliary operations, the changes in laparoscopic and open operations over time and the number of operations per trainee each year were used to measure the growth of a laparoscopic operation and to predict future trends. A survey of attitude, management algorithm, and self-confidence for coping with unexpected events in laparoscopic cholecystectomy also was conducted for senior residents and recent graduates. RESULTS: In 2001, open cholecystectomy decreased to 28%, open common duct exploration to 27%, sphincteroplasty to 20%, of 1988 (baseline year) levels. Cholecystostomy and choledochoenteric bypass decreased to 70% and 75%, respectively. The decline began before the era of laparoscopic cholecystectomy, but accelerated after its introduction. Many of the recent graduates surveyed in one program indicated a preference for a nonsurgical, mainly endoscopic, approach for all bile duct conditions, but also for the assistance of senior surgeons in the operative management of unexpected events. CONCLUSION: The popularity of noninvasive therapy in biliary surgery significantly reduced the resident's exposure to open biliary surgery, adversely affecting their confidence in the management of unexpected events encountered during laparoscopic operations. Supplemental and remedial education measures must be instituted in training programs.

A case controlled study of laparoscopic incisional hernia repair.

BACKGROUND: Although the feasibility of laparoscopic incisional herniorrhaphy has been demonstrated, its advantages over the open technique are still unproven. METHODS: Fourteen consecutive laparoscopic incisional hernia repairs were compared with 14 matched controls of the open repair done by the same surgeon at the same institution. The controls were selected by a medical record technician not connected with the study. The cases were selected to match diagnoses, ASA status, and body weight as closely as possible. The outcome data for operating time, blood loss, hospitalization, resumption of oral intake, and postoperative complications were analyzed for statistically significant differences. RESULTS: There was no statistical difference between the two groups in the parameters of blood loss, hospital days, or days to oral intake. The laparoscopic operation took 40% longer. Similar complications were seen in both groups. No mortality or early recurrences occurred in either group. CONCLUSION: Laparoscopic incisional hernia repair of at least moderate complexity had no demonstrable advantage over the open repair in the present study.

Enhancement of electrolaryngeal speech by adaptive filtering.

Artificial larynges provide a means of verbal communication for people who have either lost or are otherwise unable to use their larynges. Although they enable adequate communication, the resulting speech has an unnatural quality and is significantly less intelligible than normal speech. One of the major problems with the widely used Transcutaneous Artificial Larynx (TAL) is the presence of a steady background noise caused by the leakage of acoustic energy from the TAL, its interface with the neck, and the surrounding neck tissue. The severity of the problem varies from speaker to speaker, partly depending upon the characteristics of the individual's neck tissue. The present study tests the hypothesis that TAL speech is enhanced in quality (as assessed through listener preference judgments) and intelligibility by removal of the inherent, directly radiated background signal. In particular, the focus is on the improvement of speech over the telephone or through some other electronic communication medium. A novel adaptive filtering architecture was designed and implemented to remove the background noise. Perceptual tests were conducted to assess speech, from two individuals with a laryngectomy and two normal speakers using the Servox TAL, before and after processing by the adaptive filter. A spectral analysis of the adaptively filtered TAL speech revealed a significant reduction in the amount of background source radiation yet preserved the acoustic characteristics of the vocal output. Results from the perceptual tests indicate a clear preference for the processed speech. In general, there was no significant improvement or degradation in intelligibility. However, the processing did improve the intelligibility of word-initial non-nasal consonants.

Phosphatidylinositol 3-kinase binds to profilin through the p85 alpha subunit and regulates cytoskeletal assembly.

Phosphatidylinositol 3-kinase (PI3-K), endowed with catalytic (110kDa) and regulatory (85kDa) subunits co-precipitates with anti-tyrosine antibodies in mitogen-activated cells. Association of PI3-K with cytoskeleton activates its catalytic activity through undeciphered mechanisms. Recently Singh et al., (Biochemistry, 35, 16544-16549, 1996) have shown that profilin activates PI3-K activity in a concentration-dependent manner. Consequently, we investigated the interaction between the PI3-K and profilin employing the GSTp85 alpha fusion protein and the results indicate a specific interaction between profilin and p85 alpha. The effect of p85 alpha/profilin complex on polymerization of actin monomers was monitored fluorimetrically employing pyrene-labelled actin monomers. It was noted that p85 alpha/profilin complex inhibits actin polymerization suggesting that profilin can simultaneously bind to actin as well as to p85 alpha. The affinity of p85 alpha/profilin complex to actin increases in the presence of p85 alpha subunit of PI3-K as compared to profilin itself.

Unsuspected choledocholithiasis first diagnosed at laparoscopic cholecystectomy: treatment by trans-cystic duct stenting and elective stent-guided sphincterotomy.

BACKGROUND: Despite advances in laparoscopic surgery, management of unsuspected choledocholithiasis diagnosed at laparoscopic cholecystectomy is controversial. We propose a simple maneuver of laparoscopic trans-cystic duct stenting of the papilla during cholecystectomy, followed by elective stent-guided sphincterotomy, as an expedient option. METHODS: We studied retrospectively 16 patients with choledocholithiasis first diagnosed in the course of laparoscopic cholecystectomy, treated with laparoscopic stenting of the papilla via the cystic duct using a short Cotton-Leung stent before completion of cholecystectomy. Elective stent-guided, needle-knife sphincterotomy and stone clearance was performed 2 to 3 weeks postoperatively. RESULTS: Of 16 patients attempted, the procedure failed in one due to an impacted stone that prevented passage of the guidewire. Stenting time was 13 +/- 5 minutes (n = 15). Two stented patients had no stones at endoscopic retrograde cholangiography. Thirteen patients had successful elective stent-guided sphincterotomy with stone clearance without complications. CONCLUSIONS: Laparoscopic biliary stenting combined with stent-guided sphincterotomy is a simple, safe, and cost-effective option for the management of uncomplicated choledocholithiasis.

Efficacy of routine laparoscopy for the acute abdomen.

BACKGROUND: Laparoscopic surgery of selected acute abdominal conditions has been shown to be highly effective. Therefore, we investigated the diagnostic accuracy and therapeutic efficacy of routine laparoscopic surgery for the acute abdomen. METHODS: After appropriate investigations, patients with acute abdomen, with or without a specific diagnosis, were offered the options of either laparoscopic or open surgery. Postoperatively, we analyzed the outcome measures of diagnostic accuracy, complications, and operating time of laparoscopy. The hospital stays for our patients were compared to case-matched controls. RESULTS: The accuracy of laparoscopic diagnosis is the same as laparotomy. The 62% of our patients who were managed totally laparoscopically required shorter hospitalization than the case-matched controls treated by open operation. Morbidity was not increased by laparoscopy in patients who required conversion to open operation. The additional cost of laparoscopy appeared modest. CONCLUSIONS: Routine laparoscopy for the acute abdomen is safe and accurate. Patients eligible for laparoscopic treatment also require less hospitalization time.

Second-look laparoscopy for visceral ischemia facilitated by preinstalled ports.

Much of the information of a second-look laparotomy can be obtained by a second-look laparoscopy. We describe the strategy and technique of installing laparoscopy ports at the end of the primary laparotomy for visceral ischemia to facilitate a second-look laparoscopy in the ensuing 72 hours. The advantages and limitations are illustrated by three cases. The primary advantage appears to be that when second-look laparoscopy can be accomplished at a minimal cost, much of the inhibition to use it is removed. However, more experience is necessary before the procedure can be used to replace laparotomy.

Effect of inhaled terbutaline on platelet activity in bronchial asthma.

Thirty five young subjects with long standing bronchial asthma were studied for the effects of terbutaline misthaler (500 micrograms) during acute asthma. Bronchodilators were omitted for a day before the test. Ten matched controls were also studied. In all subjects, basal IgE level (ELISA), pulmonary parameters (FVC, FEV, PEFR, FEF 25-75 and FEF 75-85) and platelet activity, (platelet clumping/150 WBC on smear, platelet adhesiveness, blood recalcification time and kaolin clotting time for platelet factor3) were compared. During acute asthma, the subjects displayed IgE levels > or = 500 IU/ml (n = 33), activation of clotting (n = 30) and eosinophilia > or = 450/cmm (n = 28). These changes were not seen in normal controls. Terbutaline resulted in a reversal of airway obstruction, mainly of small airways, while the platelet hyperactivity and blood hypercoagulability were rectified (P < 0.001). It is concluded that platelet activity increases in acute asthma and is corrected by inhaled terbutaline concomittant with the relief of bronchospasm.

Laparoscopic placement of a percutaneous endoscopic gastrostomy (PEG) feeding tube.

Patients may have abnormal anatomic relationships between the stomach and adjacent organs, particularly when there is a history of abdominal surgery and adhesion formation. Routine placement of a percutaneous endoscopic gastrostomy tube can then be unsafe and result in inadvertent colon perforation, small bowel enterotomy, or injury to other structures. Described herein is a 94-year-old malnourished male in whom the colon lay directly anterior to the greater curvature of the stomach. A new technique was devised--laparoscopically-directed PEG placement--which proved to be a safer alternative approach in this patient.

Immunoglobulins and allergy mediators in bronchial asthma.

Seventy four young asthmatics were evaluated to establish the role of immunoglobulins and allergy mediators in clinical asthma. They were categorized into Group I (n = 38) or Group II (n = 36) when having mild or severe bronchospasm respectively. In some patients, reversibility of bronchospasm (n = 35), exercise challenge (n = 24) and intradermal allergy testing (n = 24) were also studied. Seventy subjects had raised IgE levels (greater than 100 KU/L) but these did not correlate with the severity of clinical or exercise induced asthma or with reversibility of bronchospasm. An IgE level greater than 1000 KU/L was associated with more number of positive skin tests. Group II subjects had a shorter blood recalcification time (p less than 0.01) and higher levels of IgG, histamine and serotonin (p less than 0.001). It appears that severe asthma is associated with activation of blood coagulation, and release of allergy mediators contributes to the evolution of bronchospasm. Total IgE predicts the utility of skin testing in asthma.

Prostheses and the forward reach of sitting lower-limb amputees.

The hypothesis that prostheses improve the forward reach of sitting lower-limb amputees was tested. While sitting with only ischial support, ten unilateral below-knee (BK) amputees could reach farther when they wore their prostheses than when they did not, when reaching at 45 degrees toward or away from the side of the amputation, with mean differences (+/- 1 SD) of 10.7cm (+/- 6.9, p less than 0.0001) and 4.4cm (+/- 4.1, p less than 0.01), respectively. With ten unilateral above-knee (AK) amputees, the differences were not statistically significant. Seven bilateral amputees (mixed levels) were able to reach farther with their prostheses on than off, with mean differences of 41.2cm (+/- 9.5) and 31.5cm (+/- 7.9) for reaches at 0 degrees and 45 degrees, respectively (p less than 0.0001). With the prostheses off, their reach was significantly greater when their thighs were supported than when they were sitting with only ischial support. These findings suggest that (1) prostheses improve the anterolateral reach of unilateral BK amputees, and the straight forward and anterolateral reach of bilateral amputees; (2) when prostheses are not being worn, a sitting surface which provides support through the residual limbs improves forward reach; and (3) the design of AK prostheses should reflect the patient's needs, both standing and sitting.

Lower-limb influence on sitting balance while reaching forward.

To test the hypothesis that the lower limbs contribute to sitting balance when a person reaches forward, we measured the limits of forward reach in 20 healthy volunteers. While sitting on the buttocks alone (ischial support) or with the thighs also supported and with both feet on, one foot off, or both feet off the floor (in a balanced order), each subject reached as far forward as possible at table height at 0, 15, 30, and 45 degrees to the sagittal plane. With full thigh support the reaches at all angles were greatest with both feet on the floor, and decreased progressively with one foot off (when reaching toward the foot off the floor) and both feet off. Thigh support permitted significantly greater reach than ischial support at all angles with both feet off the ground, but not in other settings. These results have implications for seat design and when considering prostheses for patients unlikely to walk.

Constituents of local plants.

The antispasmodic principle of Cymbopogon proximus has been identified as cryptomeridiol (5) from its spectral properties and comparison with an authentic sample.

[Structure of silandrin and silymonin, two new flavanolignans from a white blooming Silybum marianum variety]. / Struktur von Silandrin und Silymonin, zwei neuen Flavanolignanen aus einer weißblühenden Silybum marianum Varietät.

The structures of two flavanolignans, (-) silandrin and (+) silymonin, from a white flowering variety of Silybum marianum, have been elucidated as 3-desoxy-isosilybin and 3-desoxy-silydianin partly by spectroscopic investigations, partly by chemical transformation into other derivatives and their partial synthesis. In addition 5,7-dihydroxy-chromone has been isolated as a new compound.