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.

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.

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.

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.

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.

Relationships between pHi and tension in isolated rat mesenteric resistance arteries.

Investigations into the relationship between pHi and tension were carried out in rat mesenteric resistance arteries. Acute acidosis, induced by ammonium chloride pre-pulse, led to variable and transient tension development, but simultaneous removal of extracellular sodium led to a sustained rise in tension associated with maintained intracellular acidification. Dependence of tension and pHi recovery from acute acidosis on Na/H exchange and anion exchange pathways was demonstrated using pharmacological inhibitors. Additionally, removal of HCO3 suggested the anion pathway involved was Na-dependent HCO3 transport. Removal of extracellular calcium, or pharmacological inhibition of voltage-dependent calcium channels, prevented the tension development in response to NH4Cl pre-pulse in an Na-free medium, but did not affect pHi. Intracellular acidosis resulting from elevation of the PCO2 resulted in initial vasoconstriction followed by profound vasodilatation of arteries pre-contracted with noradrenaline (NA). The response to alkalosis induced by NH4Cl or by lowering the PCO2 led to initial dilatation followed by potentiation of NA-induced tension.

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.

Condensing osteitis of the clavicle: a rare but frequently misdiagnosed condition.

Condensing osteitis of the clavicle is a benign, often painful disorder, marked by bony sclerosis at the sternal end of the clavicle. It can be mistaken for other abnormalities such as Friedrich disease, bone island, osteoid osteoma, sternoclavicular osteoarthritis, and even a metastasis and osteosarcoma. Clinical, radiologic, scintigraphic, and histologic features of this condition are discussed and a brief overview of the treatment is provided. Three histologically proved cases are added to the 13 previously reported in the literature. Recognition of condensing osteitis of the clavicle may avoid the occasional unnecessarily aggressive diagnostic approach taken to search for a malignant tumor.

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.

Experimental study in rat metatarsals to determine whether callus vascularity is an indicator of the mechanical strength of healing fractures.

Changes in the mechanical properties and percentage area of blood vessels of healing fracture callus were followed using rat metatarsals. By 24 weeks after fracture the mean ultimate tensile stress and elastic modulus were still less than half that of the contralateral unfractured bone, whereas the mean torsional modulus had almost reached that of the unfractured bone. The percentage area of blood vessels declined from five days post-fracture and showed no changes which coincided with the increases in mechanical strength or moduli. We conclude that studies of vascularity would not justify a prediction of the strength of a healing fracture.

Commitment patients in a private psychiatric hospital: a pilot program in Tennessee.

This paper surveys the epidemiological characteristics of the first 100 patients committed to a new private psychiatric hospital in Upper East Tennessee, under a pilot program of the Tennessee Department of Mental Health and Mental Retardation. The number of psychiatric commitments in the region has increased since the opening of a local hospital required, by contract, to accept them. While all commitments were because of a psychiatric diagnosis, many patients might have been treated as outpatients had their illness not been complicated by substance abuse. Greater integration of all levels of psychiatric care would make it possible for such patients to receive care in settings more appropriate to their condition before they experience a crisis requiring inpatient commitment.

Ultrastructure and cytogenetics in seven cases of acute promyelocytic leukaemia (APL).

In the seven cases of acute promyelocytic leukaemia (APL) presented here we have studied the ultrastructural and cytogenetic features which are thought to be of particular significance in this disease. On the basis of our findings from the seven cases of APL described in detail, and our unreported results obtained for a large number of myeloid leukaemias other than APL, we conclude the following. Stellate rough endoplasmic reticulum, certain inclusion bodies and Auer rods having a tubular substructure are, if present, probably diagnostic of APL. However, these structures are not always observed in APL. Inflated rough endoplasmic reticulum is highly indicative of APL while slender cytoplasmic projections, convoluted or lobed nuclei and conspicuous bundles of cytoplasmic fibrils are very common in the abnormal promyelocytes of this disease. There is a strong correlation between the presence of conspicuous bundles of cytoplasmic fibrils and convoluted or lobed nuclei. Most of the APL cases showed the characteristic translocation t(15;17) and we could find no ultrastructural difference between the cases with the translocation and the single example of a normal karyotype.

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.

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.

8;21 translocation in acute granulocytic leukaemia: cytological, cytochemical and clinical features.

Thirty patients with the 8;21 translocation and three with closely related variants have been studied. Ages ranged from 3 to 64 years (mean 28.3). Thirty-one were entered into the MRC's 8th Acute Myeloid Leukaemia Trial. Twenty-nine (88%) achieved complete remission. Marrow smears from most patients showed granulocytic maturation (M2, FAB classification) with characteristic abnormalities, but at least six showed predominantly myeloblastic (M1) morphology. The blast cells were markedly heterogeneous with regard to size and nuclear cytoplasmic ratio. Typical staining patterns were observed in the blast cells using Sudan black B and diaminobenzidine peroxidase stains, and to a lesser extent with periodic acid-Schiff and chloroacetate esterase. Butyrate esterase was negative in all cases. Auer rods were present in the granulocyte precursors in 31 cases and in eosinophil precursors in two cases. In most cases the existence of the translocation was predicted from the cytological and cytochemical findings. Seven patients developed solid leukaemic deposits, principally in the mastoid cavities, orbital cavities or thoracic spine (extradural).