The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge.

BACKGROUND: Interleukin 13 (IL13) is a T-helper type 2 (Th2) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma. We have shown that treatment with lebrikizumab, an anti-IL13 monoclonal antibody, significantly improves prebronchodilator forced expiratory volume in 1 s (FEV(1)) in a subset of subjects with uncontrolled asthma. OBJECTIVE: To evaluate efficacy and safety of lebrikizumab in subjects with mild asthma who underwent bronchial allergen challenge. METHODS: Twenty-nine subjects were randomized 1 : 1-5 mg/kg lebrikizumab (n = 13) or placebo (n = 16) administered subcutaneously every 4 weeks over 12 weeks, a total of four doses. Primary efficacy outcome was late asthmatic response (LAR) at Week 13, defined as area under the curve of FEV1 measured 2-8 h following inhaled allergen challenge. Serum biomarkers were measured to verify IL13 pathway inhibition and identify patients with an increased response to lebrikizumab. RESULTS: At Week 13, the LAR in lebrikizumab subjects was reduced by 48% compared with placebo subjects, although this was not statistically significant (95% confidence interval, -19%, 90%). Exploratory analysis indicated that lebrikizumab-treated subjects with elevated baseline levels of peripheral blood eosinophils, serum IgE, or periostin exhibited a greater reduction in LAR compared with subjects with lower baseline levels of these biomarkers. Lebrikizumab exerted systemic effects on markers of Th2 inflammation, reducing serum immunoglobulin E (IgE), chemokine ligands 13 and 17 by approximately 25% (P < 0.01). Lebrikizumab was well tolerated. CONCLUSION AND CLINICAL RELEVANCE: Lebrikizumab reduced the LAR in subjects with mild asthma. Clinical trial number NCT00781443.

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

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

Harvest of human bone marrow directly from bone.

Harvest of human bone marrow directly from freshly resected bone provides purer preparations of marrow than can be obtained by the conventional technique of multiple aspirations from the iliac crests. In particular, directly harvested marrow is much less heavily contaminated with peripheral blood lymphocytes, a known source of mature T cells. Because of the possible relevance of these contaminating T cells for cadaveric bone marrow transplants, the best source of human marrow harvested directly from bone has been studied. Human bone marrow was harvested from 46 surgical specimens and 9 cadaveric tissue donors. Vertebral bodies provided the best source of bone marrow with average yields of 3.1 +/- 1.6 X 10(9) cells per vertebra. When entire ilia were removed and processed for marrow, an average of 1.6 +/- 1.0 X 10(9) cells was obtained. Surgically resected ribs yielded lower amounts of marrow with a mean cell number of 3.2 +/- 2.6 X 10(8) per rib. Isolation of bone marrow mononuclear cells from these preparations by density gradient centrifugation resulted in a loss of 45% of the starting cells. Human bone marrow was found to contain 5-6% T cells before gradient separation and these cells were immunologically competent as measured in vitro by responses to mitogens and alloantigens. This technique may be useful in obtaining human bone marrow for both immunologic studies and allogeneic transplantation.

A case of erythroleukaemia with homogeneously staining regions on chromosomes.

A case of erythroleukaemia with homogeneously staining regions on chromosomes is described. The number of chromosomes in bone marrow cells varied from 41 to 46 with a mode of 43. A variety of structural and numerical chromosomal abnormalities was observed. Two marker chromosomes with homogeneously staining regions were found in all aneuploid cells examined. Intensive chemotherapy failed to induce a remission and the patient died 3.9 months after diagnosis. The relation of the homogeneously staining regions on chromosomes to the two courses of chemotherapy prior to cytogenetic study is discussed.

A further study on quicker re-entry of chromosomally abnormal cells to active proliferation and preferential death of chromosomally normal cells during ageing of specimens in acute myeloid leukemia (AML).

Quicker re-entry of chromosomally abnormal cells to active proliferation under culture conditions was observed in cultured peripheral blood samples, old or fresh, but not in cultured bone marrow samples. In 10 patients with AML studied using peripheral blood, the mitotic index (MI) rose after 24 h in culture and reached a peak after 48 h in culture in AA patients (with all abnormal karyotypes); the MI rose after 24 h in culture and reached a peak after 48, 72 or 96 h in culture in AN patients (mixed normal and abnormal karyotypes); the MI remained at much lower level until after 72, 96 or 120 h of culture in NN patients (all normal karyotypes). The MI at 24 and 48 h of culture was significantly higher in AN and AA patients than in NN patients. A significantly increased frequency of chromosomally normal cells after prolonged culture was observed in one patient with t(8;21). The results of this study also suggest that chromosomally normal cells are more likely to die off than are abnormal ones during ageing of specimens.

Analysis of G banded karyotypes in myeloma cells.

Karyotypes of bone marrow cells from 24 patients with multiple myeloma (MM) and two patients with de novo plasma cell leukaemia (PCL) were analysed by Giemsa banding (G banding). Chromosome aberrations were found in 13 patients with MM and both patients with PCL. Hyperdiploid and hypodiploid lines were present in eight and five of the patients with MM, respectively. Marker chromosomes derived from structural rearrangements were present in all eight cases of MM with hyperdiploid lines, although markers of uncertain origin were rare in those patients with hypodiploid lines. Chromosome 1 participated most often, and chromosomes 5 and 9 often played a part in the structural rearrangements. Chromosomes 3, 5, 7, 9, 11, 15, 19, and 21 were subject to numerical aberrations. In the two patients with PCL one had a hypodiploid line with a 14q + marker derived from a t(11;14) and the other a hyperdiploid line. The breakpoints on the chromosomes participating in the structural rearrangements in myeloma showed a good correlation with known fragile sites and oncogene locations on the corresponding chromosomes.

An unusual translocation, t(3;8), and deletion of chromosome 21 in acute myeloid leukemia.

This report describes a case of acute myeloid leukemia (AML) in which there was an unusual karyotypic abnormality involving chromosomes #3, #8, and #21. The clinical and hematologic features are described and cytogenetic findings are discussed in relation to previously reported variants of the translocation t(8;21) in AML. The breakpoint at 8q22 is a consistent feature in these cases.

Groups of darkly stained chromosomes may be artifacts.

Groups or conglomerations of darkly stained chromosomes (GDSC) observed in this study appeared to be artifacts as they were strictly technique dependent. Two methods of cell fixation were compared. In method I, fixative was added drop by drop to cell pellets and agitated continuously over a rotamixer. In method II, a few drops of fixative were added to hypotonic solution suspended with cells and mixed using a Pasteur pipette. In 11 patients with acute myeloid leukemia (AML) and in one patient with preleukemia studied using method I, no GDSC were found in the total of 325 metaphases examined. In 36 patients with AML, one with Klinefelter's syndrome and one with neutropenia studied using method II, GDSC were found in 18 patients. A further comparative study using different methods for cell fixation was performed in three patients. The frequency of cells with GDSC varied sharply with different methods used in two patients. In one patient the cells with GDSC were analyzed in detail. The number of darkly stained chromosomes in each cell was found to vary from 4 to 14 with a mean of 8.26 and D- and G-group chromosomes were preferentially involved.

Pneumonia in patients with multiple trauma.

This article examines the features of nosocomial pneumonia in the subpopulation of patients with multiple trauma. Epidemiology, trauma-associated risk factors, diagnosis, microbiology, therapy, and prevention are reviewed. While some issues may overlap with critically ill patients in general, differences in approach and management will be discussed.

Endoprosthetic reconstruction after bone tumor resections of the proximal tibia.

The advent of successful adjuvant chemotherapy and radiation therapy protocols for primary malignant tumors and the development of custom-designed metallic endoprostheses has now made possible a successful limb salvage procedure for malignancies of the proximal tibia. Use of the transposed medial gastrocnemius flap, as proposed by Dr. Jean Duboussett of Paris, has been critical to the soft-tissue reconstruction that routinely permits an excellent active and passive range of motion for these patients. This article describes the operative techniques and technical considerations necessary for a successful proximal tibial endoprosthesis reconstruction.

Fading characteristics of a 2.3 GHz radio telemetry channel in a hospital building.

This paper reports on radio path attenuation measurements made in a hospital complex at a spot frequency of 2.340 GHz. Power loss figures for fixed path propagation in a variety of building types have been determined for proposed telemetry use in operational ward situations. Throughout the hospital, the radio paths assessed all exhibited a loss in excess of that calculated for free-space communications. Modern buildings had external wall losses of 10-25 dB, with dividing walls in wards contributing an additional 5 dB. Received signal strength levels indicated a Rayleigh distribution for obstructed paths. Temporal testing was used to find the rate and depth of signal fades caused by the movement of personnel and equipment during normal ward usage; signal level reductions of greater than 35 dB were common during busy periods.

Changes in plasma enzyme activities and other blood components in response to acute and chronic liver damage in cattle.

Three calves were dosed orally with carbon tetrachloride at 0.05, 0.1 or 0.3 ml/kg body-weight. Plasma enzyme activities, clotting times, bilirubin concentrations and bromsulphthalein elimination times increased. These changes are associated with damage to the liver and are discussed in relation to the clinical syndrome. Three groups of seven calves were infected weekly with 10, 50 or 100 Fasciola hepatica metacercariae for 12 consecutive weeks. Maximum glutamate dehydrogenase and gamma glutamyltransferase activities in the plasma were greater with the larger infecting doses but there was no change in plasma clotting times.

Feed associated haemorrhagic disorder in pigs accompanied by pancreatic lesions.

The introduction of a new batch of feed to 400 pigs aged five to eight weeks resulted in 38 deaths and further morbidity associated with multiple haemorrhages. Signs abated within two days of withdrawal of the feed. Widespread haemorrhages were present in many tissues including the pancreas. Additional pancreatic lesions comprised focal necrosis, atrophy and fibrosis of exocrine tissue. The condition was reproduced experimentally in pigs and vitamin K protected mice against the injurious effects of the feed. The cause was not determined but it is speculated that more than one toxic factor and an imbalance of nutritional factors may have been present in the diet.

The failure of trichothecene mycotoxins and whole cultures of Fusarium tricinctum to cause experimental haemorrhagic syndromes in calves and pigs.

Piglets and calves were dosed orally with pure diacetoxyscirpenol (DAS) and T-2 toxin, crude extracts of Fusarium tricinctum containing T-2 toxin, and whole cultures of F tricinctum containing T-2 toxin at a constant daily rate of 0.1 mg toxin per kg body-weight (piglets) or 0.2 mg toxin per kg body-weight (calves). The treatment continued for periods of seven to 78 days but it failed to induce clinical haemorrhagic syndromes. Increasing the dose of F tricinctum culture five-fold for eight days following 78 days at the lower dose was equally ineffective. The lack of an effect by daily intakes of toxin that could have been ingested with naturally contaminated feedstuffs suggests that DAS, T-2 toxin and other metabolites of F tricinctum probably have little or no part to play in the aetiology of feed associated haemorrhagic disease.

Improving care: a study of orthopaedic outpatient referrals.

OBJECTIVE: To identify aspects of outpatient referral in which general practitioners', consultants', and patients' satisfaction could be improved. DESIGN: Questionnaire survey of general practitioners, consultant orthopaedic surgeons, and patients referred to an orthopaedic clinic. SETTING: Orthopaedic clinic, Doncaster Royal Infirmary. SUBJECTS: 628 consecutive patients booked into the orthopaedic clinic. MAIN OUTCOME MEASURES: Views of the general practitioners as recorded both when the referral letter was received and again after the patient had been seen, views of the consultants as recorded at the time of the clinic attendance, and views of the patients as recorded immediately after the clinic visit and some time later. RESULTS: Consultants rated 213 of 449 referrals (42.7%) as possibly or definitely inappropriate, though 373 of 451 patients (82.7%) reported that they were helped by seeing the consultant. Targets for possible improvement included information to general practitioners about available services, communication between general practitioners and consultants, and administrative arrangements in clinics. Long waiting times were a problem, and it seemed that these might be reduced if general practitioners could provide more advice on non-surgical management. Some general practitioners stated that they would value easier telephone access to consultants for management advice. It was considered that an alternative source of management advice on musculoskeletal problems might enable more effective use to be made of specialist orthopaedic resources. Conclusion--A survey of patients' and doctors' views of referrals may be used to identify aspects in which the delivery of care could be made more efficient. Developing agreed referral guidelines might help general practitioners to make more effective use of hospital services.

High tibial osteotomy without internal fixation for medial unicompartmental osteoarthrosis.

Between 1982 and 1993, a total of 35 patients underwent high tibial osteotomy for medial unicompartmental osteoarthrosis. The osteotomy was performed high in the tibia without the use of jigs, and internal fixation devices were avoided. Patients were assessed using the British Association for Surgery of the Knee score, and satisfactory results with minimal complications were obtained. Our results indicate that in a select group of patients, high tibial osteotomy preserves bone stock and is performed near the deformity so that excellent correction is achieved and recurrence of varus deformity is avoided.