Phase 2a, randomized, double-blind, placebo-controlled, multicentre, parallel-group study of an H4 R-antagonist (JNJ-39758979) in adults with uncontrolled asthma.

BACKGROUND: The effects of H4 R antagonists in preclinical asthma models support the study of antagonists of the H4 R in the treatment of asthma in humans. JNJ-39758979 is a potent and highly selective oral H4 R antagonist. OBJECTIVE: We sought to evaluate the safety and efficacy of the H4 R-antagonist JNJ-39758979 in adult patients with uncontrolled asthma. METHODS: One hundred and fifteen eligible patients were randomly assigned to JNJ-39758979 300 mg or placebo once daily for 12 weeks in this phase 2a, double-blind, multicenter, placebo-controlled study. Primary efficacy was assessed via week-12 change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1 ). Secondary efficacy assessments included patient-reported outcome (PRO) asthma assessments (Asthma Daily Diary data [AM and PM peak expiratory flow rate, number of puffs of albuterol/salbutamol, the presence of nocturnal awakenings and asthma symptom score]). RESULTS: The study did not meet the primary end-point. However, nominally significant improvements in pre-bronchodilator FEV1 were observed with JNJ-39758979 versus placebo at week 12 in pre-specified subgroups with elevated exhaled nitric oxide, sputum eosinophils or blood eosinophils at baseline. Nominally significant improvements across PRO assessments were consistently observed in the overall population, as well as in eosinophilic subgroups. Safety, such as adverse event rates, was comparable between JNJ-39758979 and placebo. No serious adverse events were reported. No clinically relevant changes in laboratory values were observed. CONCLUSIONS AND CLINICAL RELEVANCE: The findings suggest potential benefit of H4 R antagonists on lung function and asthma control in eosinophilic asthma patients and warrant further evaluation of this mechanism in asthma with eosinophilic inflammation. NCT00946569.

The effect of counting principal and secondary injuries on national estimates of motor vehicle-related trauma: a NEISS-AIP special study.

OBJECTIVE: To demonstrate the effect of including both principal and secondary injuries in the calculation of national estimates of non-fatal motor vehicle-related injury, using the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP). METHODS: The setting was a stratified sample of 15 US hospital emergency departments selected among 50 NEISS-AIP hospitals which agreed to participate in the study. Non-fatal injury data from a special study of the 2004 NEISS-AIP were analysed which allowed up to five injuries to be coded per case. National estimates of number and rate of injuries for 2004 were calculated, first using principal injuries alone, then by including principal and secondary injuries. RESULTS: An estimated 4,833,626 principal and secondary injuries were sustained by the estimated 2,893,782 motor vehicle occupants involved in a crash and treated in US hospital emergency departments (EDs) in 2004. This represents a 67% increase in the total number of injuries compared with an estimate of principal injury alone. Incidence of contusions/abrasions and lower trunk injuries rose most steeply among broad injury types, and whiplash injury rose 18% in number and rate. A significantly lower percentage of cases with a single listed injury were hospitalised (5%) compared with those who sustained multiple injuries (8%). CONCLUSIONS: Based on an analysis of NEISS-AIP special study data, the inclusion of both principal and secondary injuries in national estimates of motor vehicle-related occupant injury would provide a more comprehensive report of non-fatal injuries treated in US hospital EDs. Other countries with ED-based surveillance systems could consider reporting multiple injuries when assessing injury count associated with motor vehicle trauma requiring ED care.

Randomized, controlled, dose-ranging trial of carisbamate for partial-onset seizures.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of carisbamate (CRS), an investigational drug, as adjunctive treatment for partial-onset seizures in adults. METHODS: A randomized, double-blind, placebo-controlled, multicenter, dose-ranging study was conducted in 12 countries. Patients counted seizures during an 8-week baseline period, and then, if eligible, entered a double-blind phase consisting of a 4-week dose-titration period (target CRS doses: 100, 300, 800, or 1,600 mg/d or placebo in two divided doses) and a 12-week maintenance period. The primary efficacy variable was percent reduction in partial-onset seizure frequency during the double-blind phase compared with pretreatment baseline. Safety data and responder rates were also assessed. RESULTS: Five hundred thirty-seven patients were randomized, and 82% completed the study. In the intent-to-treat population (n = 533), CRS at doses of > or =300 mg/d (p < or = 0.006) reduced the frequency of partial-onset seizures vs placebo: 6% (placebo) vs 24% (300 mg/d), 21% (800 mg/d), and 29% (1,600 mg/d) for CRS. Adverse events consisted primarily of CNS effects, and led to discontinuation of drug in 8% of the placebo group vs 5% (100 mg/d), 6% (300 mg/d), 12% (800 mg/d), and 19% (1,600 mg/d) of the CRS groups. CONCLUSIONS: Carisbamate at doses of 300, 800, and 1,600 mg/d was effective as adjunctive therapy for reducing the frequency of partial-onset seizures.

Evaluation of risperidone in the treatment of behavioral and psychological symptoms and sleep disturbances associated with dementia.

BACKGROUND: Dementia is associated with progressive cognitive impairment and behavioral and psychological symptoms. Sleep-wake cycle disturbances are common in patients with dementia. This study evaluated the efficacy and safety of risperidone in the treatment of the behavioral and psychological symptoms of dementia (BPSD) and associated sleep-wake cycle disturbances. METHODS: In this open-label, 12-week, observational, prospective study, the effects of risperidone were assessed using the Neuropsychiatric Inventory (NPI) total and subscale scores. Sleep-wake cycle disturbances were rated by patients/caregivers using a newly developed sleep behavior questionnaire that included assessment of sleep duration, quality, awakenings, and effects on daily activities. Tolerability assessments included the Udvalg for Kliniske Undersogelser (UKU) subscale for extrapyramidal symptoms (EPS) and the recording of adverse events. RESULTS: A total of 338 patients entered the study, with 321 patients completing. Following 12 weeks of risperidone treatment (mean dose 1.49 mg/day at end-point), the mean NPI score was reduced to 10.6 from a baseline score of 28.7. Compared with baseline, patients/caregivers reported significant improvements following 12 weeks of risperidone in total sleep hours at night (5.5 vs. 7.1 hours), hours awake in bed at night (2.3 vs. 1.2 hours), insomnia (40.1% vs. 8.4%), and other sleep-related variables. Six patients reported a total of 10 adverse events, including somnolence (n = 3) and sialorrhea (n = 2). Scores on the UKU subscale of EPS improved significantly (mean 4.0 at baseline vs. 1.7 at week 12). CONCLUSIONS: Risperidone is effective and well tolerated in the treatment of BPSD and associated sleep disturbances.

A study design to investigate the effect of intense Tai Chi in reducing falls among older adults transitioning to frailty.

This paper describes the study design, methodological considerations, and baseline characteristics of a clinical trial to determine if intense (48 weeks, twice per week) Tai Chi practice can reduce the frequency of falls among older adults transitioning to frailty compared to a wellness education program. Twenty facilities will be stratified on socioeconomic status and facility type and randomly assigned to one of the two interventions. Secondary outcome measurements include variables related to function, behavior, and the biomechanics of movement. This study is unique because it represents an effort to offer a novel physical intervention to a large sample of transitional frail adults, a population that has received few formal exercise interventions. In addition to bringing the interventions into facilities, a 1-year follow-up is also included to assess rates of change in outcome measurements.

Evolving indications for permanent pacemakers.

New indications for permanent cardiac pacing have been developed in recent years, with numerous studies demonstrating improved clinical outcomes in a variety of disorders. Because hypertrophic obstructive cardiomyopathy, dilated cardiomyopathy, heart failure, neurocardiogenic syncope, and atrial fibrillation are common conditions, every clinician should be aware of evolving alternative therapies for them. Observational studies in patients with refractory, symptomatic hypertrophic obstructive cardiomyopathy and significant left ventricular outflow gradient at rest suggest that cardiac pacing may result in symptomatic and hemodynamic improvement. Clinical trials have not shown conclusive evidence regarding the long-term benefit from pacing in these patients, and it is unclear whether pacing will be a preferred treatment option. Preliminary data suggest that pacing is a viable adjunctive therapeutic approach for improving symptoms in patients with dilated cardiomyopathy and heart failure. Mortality benefit has yet to be established, but it is to be hoped that ongoing randomized clinical trials will provide definitive information on that issue. Patients with refractory neurocardiogenic syncope or those who are intolerant of medical treatment may benefit from pacing therapies, especially those that use rate-drop sensor algorithms. Biatrial pacing has emerged as a technique that resynchronizes atrial electrical activity and has been shown to prevent atrial fibrillation. Multisite atrial pacing for the prevention of atrial fibrillation is considered investigational but seems promising. Newer indications for pacing are expected to result in improved clinical outcomes for hypertrophic obstructive cardiomyopathy, dilated cardiomyopathy and heart failure, neurocardiogenic syncope, and the prevention of atrial fibrillation.

Associations of demographic, functional, and behavioral characteristics with activity-related fear of falling among older adults transitioning to frailty.

OBJECTIVES: To determine, in a cohort of older individuals transitioning to frailty (defined by Speechley and Tinetti, 1991) who have previously fallen, whether there are significant associations between demographic, functional, and behavioral characteristics and activity-related fear of falling, using both the Falls Efficacy Scale (FES) and the Activities-Specific Balance Confidence Scale (ABC). DESIGN: Baseline cross-sectional analysis in a prospective cohort intervention study. SETTING: Twenty independent senior living facilities in Atlanta. PARTICIPANTS: Seventeen male and 270 female subjects (n = 287), age 70 and older (mean +/- standard deviation, 80.9 +/- 6.2), with Mini-Mental State Examination score > or = 24, transitioning to frailty, ambulatory (with or without assistive device), medically stable, and having fallen in the past year. MEASUREMENTS: Activity-related fear of falling was evaluated with the FES and ABC Scale. Because of the comparable data derived from each scale, associations with functional measures-related analyses were expressed using the latter. Depression was measured by Center for Epidemiological Studies Depression Scale. Functional measurements included timed 360 degrees turn, functional reach test, timed 10-meter walk test, single limb stands, picking up an object, and three chair stands. RESULTS: No statistically significant association was found between activity-related fear of falling and age. For the proposed activities, about half (ABC, 48.1%; FES, 50.1%) of the subjects were concerned about falling or showed lack of confidence in controlling their balance. A statistically significant inverse correlation was found between FES and ABC (r = -0.65; P < .001). African-American subjects showed more activity-related fear of falling than did Caucasians (odds ratio (OR): 2.7 for ABC; 2.1 for FES). Fearful individuals were more likely to be depressed and more likely to report the use of a walking aid than were nonfearful individuals. Fear of falling was significantly correlated to all of the functional measurements (P < .05). In a multivariable logistic regression model, depression, using a walking-aid, slow gait speed, and being an African-American were directly related to being more fearful of falling. CONCLUSIONS: Activity-related fear of falling was present in almost half of this sample of older adults transitioning to frailty. The significant association of activity-related fear of falling with demographic, functional, and behavioral characteristics emphasizes the need for multidimensional intervention strategies to lessen activity-related fear of falling in this population.

Use and need for post-acute services following paediatric head injury.

This paper aims to document the types of inpatient and outpatient post-acute services children receive after discharge from an acute care hospital for head injury and to better understand the extent to which children fail to receive services and the reasons for not receiving needed services. A follow-up was conducted on 95 children (aged 5-15) 1 year after they were hospitalized for head injury. Parents were interviewed by phone concerning their child's use of and need for medical, rehabilitation, and social services since the injury. Questions were also asked regarding the child's current health status and behaviour. Inpatient records were reviewed to obtain information on the characteristics of the injury. Overall use of outpatient rehabilitation and social services was low during the year following injury, ranging from 0-18% of the study sample. Although need for and use of services was positively correlated with head injury severity, it appears that unmet need was highest for children with the least severe head injuries. Finally, need for physical or occupational therapy and mental health services was unrecognized for one third of children with physical limitations and 40% of children with at least 14 identified behaviour problems. These findings underscore the need for physicians and other health care professionals to thoroughly evaluate children during follow-up visits as well as during the initial hospitalization for head injury-related deficits. Identification of functional deficits or behavioural problems should be followed-up by evaluation and treatment by qualified rehabilitation professionals.

Doing it with mirrors: a case study of a novel approach to neurorehabilitation.

Arm amputees can experience the perception of movement of a phantom limb while looking at a mirror reflection of the moving, intact arm superimposed on the perceived phantom. Such use of a mirror to provide illusory visual feedback of movement can be useful in rehabilitation of hemiparetic patients. In this case report, we describe the successful application of "mirror therapy" to the post-stroke rehabilitation of a patient with poor functional use of an upper extremity, due mainly to somatosensory deficits. Mirror therapy facilitated employment of a motor copy strategy (bimanual movements) and later progression to "forced use" of the affected arm. The end result was increased functional use of the affected upper limb.

Matched-pair analysis of hematopoietic progenitor cell mobilization using G-CSF vs. cyclophosphamide, etoposide, and G-CSF: enhanced CD34+ cell collections are not necessarily cost-effective.

Using matched-pair analysis, we compared two popular methods of stem cell mobilization in 24 advanced-stage breast cancer patients who underwent two consecutive mobilizing procedures as part of a tandem transplant protocol. For the first cycle, 10 microg/kg/day granulocyte colony-stimulating factor (G-CSF) was given and apheresis commenced on day 4 and continued for < or =5 days (median 3 days). One week after the first cycle of apheresis, 4000 mg/m2 cyclophosphamide, 400 mg/m2 etoposide, and 10 microg/kg G-CSF were administered for < or =16 days (cycle 2). Apheresis was initiated when the white blood cell (WBC) count exceeded 5000 cells/microL and continued for < or =5 days (median 3 days). Mean values of peripheral blood WBC (31,700+/-3200 vs. 30,700+/-3300/microL) were not significantly different between cycles 1 and 2. Mean number of mononuclear cells (MNC) collected per day was slightly greater with G-CSF mobilization than with the combination of chemotherapy and G-CSF (2.5+/-0.21x10(8) vs. 1.8+/-0.19x10(8) cells/kg). Mean daily CD34+ cell yield, however, was nearly six times higher (12.9+/-4.4 vs. 2.2+/-0.5x10(6)/kg; p = 0.01) with chemotherapy plus G-CSF. With G-CSF alone, 13% of aphereses reached the target dose of 5x10(6) CD34+ cells/kg in one collection vs. 57% with chemotherapy plus G-CSF. Transfusions of red blood cells or platelets were necessary in 18 of 24 patients in cycle 2. Three patients were hospitalized with fever for a median of 3 days after cycle 2. No patients received transfusions or required hospitalization during mobilization with G-CSF alone. Resource utilization (cost of drugs, aphereses, cryopreservation, transfusions, hospitalization) was calculated comparing the median number of collections to obtain a target CD34+ cell dose of 5x10(6) cells/kg: four using G-CSF vs. one using the combination in this data set. Resources for G-CSF mobilization cost $7326 vs. $8693 for the combination, even though more apheresis procedures were performed using G-CSF mobilization. The cost of chemotherapy administration, more doses of G-CSF, transfusions, and hospitalizations caused cyclophosphamide, etoposide, and G-CSF to be more expensive than G-CSF alone. A less toxic and less expensive treatment than cyclophosphamide, etoposide, and G-CSF is needed to be more cost-effective than G-CSF alone for peripheral blood progenitor cell mobilization.

Bone dysplasia series. Melorheostosis: review and update.

Melorheostosis is a rare nongenetic developmental anomaly first described in 1922 by Léri and Joanny. Its etiology is unknown. Patients present at any age, and both sexes are affected equally. Onset is usually insidious, with deformity of the extremity, pain, limb stiffness and limitation of motion in the joints first manifesting in late childhood or early adolescence and progressing into adult life. The characteristic radiographic appearance consists of irregular hyperostotic changes of the cortex, generally on one side of the bone, resembling melted wax dripping down one side of a candle. This appearance gave the anomaly its name, which is taken from the Greek words for member (melos) and flow (rhein). There is usually a distinct demarcation between the affected and normal bone. Dense, sclerotic linear areas are seen mainly in the cortex but also extending into the cancellous bone. Melorheostosis affects mainly the long bones of the upper and lower limbs, but also the short bones of the hand and foot and, rarely, the axial skeleton. It may co-exist with osteopoikilosis and osteopathia striata as well as with tumours or malformations of blood vessels or lymphatics. Soft-tissue ossifications at the site of the joint are common. Bone scintigraphy is positive and shows moderately increased uptake of tracer. Computed tomography and magnetic resonance imaging can further characterize the lesion, but rarely contribute to the diagnosis. The forme fruste of melorheostosis may mimic other conditions such as myositis ossificans, osteoma and parosteal osteosarcoma. Treatment of this chronic and sometimes debilitating condition consists of surgical soft-tissue procedures and even, in very severe cases, amputation.

Hematopoietic growth factor after autologous peripheral blood transplantation: comparison of G-CSF and GM-CSF.

Autologous peripheral blood stem cell (PBSC) transplantation results in rapid hematologic recovery when sufficient numbers of CD34+ cells/kg are infused. Recent studies suggest that filgrastim (G-CSF) administration following transplantation leads to more rapid neutrophil recovery and lower total transplant costs. This study compares the use of G-CSF (5 microg/kg/day) with sargramostim (GM-CSF) 500 microg/day from day 0 until neutrophil recovery (ANC >1500/mm3) in patients with breast cancer or myeloma who had PBSC mobilized with the combination of cyclophosphamide, etoposide, and G-CSF. Twenty patients (13 breast cancer and seven myeloma) received GM-CSF and 26 patients (14 breast cancer and 12 myeloma) received G-CSF. The patients were comparable for age and stage of disease, and received stem cell grafts that were not significantly different (CD34+ x 10(6)/kg was 12.5 +/- 11.1 (mean +/- s.d.) for GM-CSF and 19.8 +/- 18.5 for G-CSF; P = 0.10). The use of red cells (2.8 vs 2.3 units), and platelet transfusions (2.5 vs 3.1) was similar for the two groups, as was the use of intravenous antibiotics (4.3 vs 4.6 days) and the number of days with temperature >38.3 degrees C (2.3 vs 1.8). Platelet recovery was also similar in both groups (platelets >50,000/mm3 reached after 11.8 vs 14.9 days). The recovery of neutrophils, however, was faster using G-CSF. ANC >500/mm3 and >1000/mm3 were reached in the GM-CSF group at 10.5 +/- 1.5 and 11.0 +/- 1.7 days, respectively, whereas with G-CSF only 8.8 +/- 1.2 and 8.9 +/- 2.2 days were required (P < 0.001). As a result, patients given G-CSF received fewer injections than the GM-CSF patients (10.9 vs 12.3). Resource utilization immediately attributable to the use of growth factors and the duration of pancytopenia, excluding hospitalization, were similar for the two groups. This study suggests that neutrophil recovery occurs more quickly following autologous PBSC transplant using G-CSF in comparison to GM-CSF, but the difference is not extensive enough to result in lower total cost.

The pathogenesis of osteonecrosis and the relationships to corticosteroids.

One of the challenging issues faced by allergists is a risk-benefit analysis on the use of corticosteroids. An uncommon, but serious complication of corticosteroids is the development of avascular necrosis (osteonecrosis). In this review we present the differential diagnosis and pathophysiology of osteonecrosis, with particular emphasis on steroids. Osteonecrosis of the femoral head is a common disorder that may be either naturally occurring or iatrogenic. With the exception of those cases labeled as idiopathic, the majority are the result of some insult to the vascular integrity of the affected hip. The reason for this disruption is manifold and can range from direct trauma to the more subtle or indirect compromise associated with fatty emboli or often an intravascular event such as that seen in sickle cell anemia. Although they are not totally understood, corticosteroids present a special problem because of susceptibility factors that may make some patients more likely to get osteonecrosis than others. The problem may be more complex, in that the association between corticosteroid use and osteonecrosis may be disease-dependent. In any case, any patient receiving long-term corticosteroids should be warned of this potentially debilitating complication.

Avascular necrosis.

There are multiple conditions associated with the development of osteonecrosis including trauma, hemoglobinopathies, Caisson disease, local infiltrative lesions, hypercortisolism, alcohol consumption, chronic renal failure, and autoimmune disease.

A musculoskeletal radiologist's view of nuclear medicine.

The introduction of cross-sectional and multiplanar imaging techniques has not diminished the value of radionuclide bone scanning. Skeletal scintigraphy remains an extremely effective and relatively inexpensive tool for diagnosis of many disorders of bones and joints. The sensitivity of scintigraphy in detecting stress fractures approaches 100%, although it is less specific than plain film radiography. However, radionuclide bone scanning can reveal subtle early changes in bone metabolism. For evaluation of infections, particularly in patients with diabetic foot neuropathy, scintigraphy is the modality of choice, although a combination of imaging techniques may be necessary in previously damaged bone. Radionuclide bone scanning has retained its place in the evaluation of primary bone tumors and metastases, and in screening of patients with metabolic bone disease. The radiologist should be aware that although this modality is generally used as an ancillary technique in conjunction with plain radiography, conventional tomography, computed tomography (CT), and magnetic resonance imaging (MRI), at times it can be used as the primary modality not only for the identification of skeletal lesions but also to provide important information required to make a definite diagnosis.

Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials.

BACKGROUND: Adapalene is a new chemical entity that exhibits tretinoin-like activities in the terminal differentiation process. OBJECTIVE: We evaluated a dose range effect of two concentrations of adapalene gel as acne treatment and compared adapalene 0.1% gel with tretinoin 0.025% gel in the treatment of acne patients in two large multicenter studies. METHODS: Multicenter, investigator-masked, parallel group studies including 89 acne patients in the dose range study and 591 patients in the concurrent controlled studies were conducted. RESULTS: Adapalene gel 0.1% was significantly more effective in treating acne lesions than 0.03% adapalene gel. Adapalene gel 0.1% was significantly more effective than 0.025% or tretinoin gel in one study and of the same effectiveness in the other study. Adapalene gel was always better tolerated than tretinoin gel. CONCLUSION: Adapalene 0.1% gel is a safe and effective treatment of acne vulgaris.