Complex organisational factors influence multidisciplinary care for patients with hip fractures: a qualitative study of barriers and facilitators to service delivery.

BACKGROUND: Hip fractures are devastating injuries, with high health and social care costs. Despite national standards and guidelines, substantial variation persists in hospital delivery of hip fracture care and patient outcomes. This qualitative study aimed to identify organisational processes that can be targeted to reduce variation in service provision and improve patient care. METHODS: Interviews were conducted with 40 staff delivering hip fracture care in four UK hospitals. Twenty-three anonymised British Orthopaedic Association reports addressing under-performing hip fracture services were analysed. Following Thematic Analysis of both data sources, themes were transposed onto domains both along and across the hip fracture care pathway. RESULTS: Effective pre-operative care required early alert of patient admission and the availability of staff in emergency departments to undertake assessments, investigations and administer analgesia. Coordinated decision-making between medical and surgical teams regarding surgery was key, with strategies to ensure flexible but efficient trauma lists. Orthogeriatric services were central to effective service delivery, with collaborative working and supervision of junior doctors, specialist nurses and therapists. Information sharing via multidisciplinary meetings was facilitated by joined up information and technology systems. Service provision was improved by embedding hip fracture pathway documents in induction and training and ensuring their consistent use by the whole team. Hospital executive leadership was important in prioritising hip fracture care and advocating service improvement. Nominated specialty leads, who jointly owned the pathway and met regularly, actively steered services and regularly monitored performance, investigating lapses and consistently feeding back to the multidisciplinary team. CONCLUSION: Findings highlight the importance of representation from all teams and departments involved in the multidisciplinary care pathway, to deliver integrated hip fracture care. Complex, potentially modifiable, barriers and facilitators to care delivery were identified, informing recommendations to improve effective hip fracture care delivery, and assist hospital services when re-designing and implementing service improvements.

'DrinkThink' alcohol screening and brief intervention for young people: a qualitative evaluation of training and implementation.

Background: Alcohol Screening and Brief Intervention (ASBI) helps reduce risky drinking in adults, but less is known about its effectiveness with young people. This article explores implementation of DrinkThink, an ASBI co-produced with young people, by health, youth and social care professionals trained in its delivery. Methods: A qualitative evaluation was conducted using focus groups with 33 staff trained to deliver DrinkThink, and eight interviews with trained participants and service managers. These were recorded, transcribed and a thematic analysis undertaken. Results: DrinkThink was not delivered fully by health, youth or social care agencies. The reasons for this varied by setting but included: the training staff received, a working culture that was ill-suited to the intervention, staff attitudes towards alcohol which prioritized other health problems presented by young people, over alcohol use. Conclusions: Implementation was limited because staff had not been involved in the design and planning of DrinkThink. Staffs' perceptions of alcohol problems in young people and the diverse cultures in which they work were subsequently not accounted for in the design. Co-producing youth focused ASBIs with the professionals expected to deliver them, and the young people whom they target, may ensure greater success in integrating them into working practice.

Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors.

BACKGROUND: Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed. RESULTS: Twenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2-81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ∼110-160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2-18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers. CONCLUSION: Ramucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors. CLINICALTRIALSGOV: NCT00786383.

Dental Extractions under General Anesthesia: New Insights from Process Mining.

INTRODUCTION: Tooth extraction under general anesthetic (GA) is a global health problem. It is expensive, high risk, and resource intensive, and its prevalence and burden should be reduced where possible. Recent innovation in data analysis techniques now makes it possible to assess the impact of GA policy decisions on public health outcomes. This article describes results from one such technique called process mining, which was applied to dental electronic health record (EHR) data. Treatment pathways preceding extractions under general anesthetic were mined to yield useful insights into waiting times, number of dental visits, treatments, and prescribing behaviors associated with this undesirable outcome. METHOD: Anonymized data were extracted from a dental EHR covering a population of 231,760 patients aged 0 to 16 y, treated in the Irish public health care system between 2000 and 2014. The data were profiled, assessed for quality, and preprocessed in preparation for analysis. Existing process mining methods were adapted to execute process mining in the context of assessing dental EHR data. RESULTS: Process models of dental treatment preceding extractions under general anesthetic were generated from the EHR data using process mining tools. A total of 5,563 patients who had 26,115 GA were identified. Of these, 9% received a tooth dressing before extraction with an average lag time of 6 mo between dressing and extraction. In total, 11,867 emergency appointments were attended by the cohort with 2,668 X-rays, 4,370 prescriptions, and over 800 restorations and other treatments carried out prior to tooth extraction. DISCUSSION AND CONCLUSIONS: Process models generated useful insights, identifying metrics and issues around extractions under general anesthetic and revealing the complexity of dental treatment pathways. The pathways showed high levels of emergency appointments, prescriptions, and additional tooth restorations ultimately unsuccessful in preventing extractions. Supporting earlier publications, the study suggested earlier screening, preventive initiatives, guideline development, and alternative treatments deserve consideration. KNOWLEDGE TRANSFER STATEMENT: This study generates insights into tooth extractions under general anesthetic using process mining technologies and methods, revealing levels of extraction and associated high levels of prescriptions, emergency appointments, and restorative treatments. These insights can inform dental planners assessing policy decisions for tooth extractions under general anesthetic. The methods used can be combined with costs and patient outcomes to contribute to more effective decision-making.

"It's crucial they're treated as patients": ethical guidance and empirical evidence regarding treating doctor-patients.

Ethical guidance from the British Medical Association (BMA) about treating doctor-patients is compared and contrasted with evidence from a qualitative study of general practitioners (GPs) who have been patients. Semistructured interviews were conducted with 17 GPs who had experienced a significant illness. Their experiences were discussed and issues about both being and treating doctor-patients were revealed. Interpretative phenomenological analysis was used to evaluate the data. In this article data extracts are used to illustrate and discuss three key points that summarise the BMA ethical guidance, in order to develop a picture of how far experiences map onto guidance. The data illustrate and extend the complexities of the issues outlined by the BMA document. In particular, differences between experienced GPs and those who have recently completed their training are identified. This analysis will be useful for medical professionals both when they themselves are unwell and when they treat doctor-patients. It will also inform recommendations for professionals who educate medical students or trainees.

A reassessment of comparative pregnancy and implantation rates following embryo transfer in recipients vs their infertile donors also trying to conceive in the background of performing salpingectomy for hydrosalpinx.

PURPOSE: To compare pregnancy and implantation rates in egg donors trying to conceive vs their recipients in the background of salpingectomy for hydrosalpinx prior to IVF-ET. METHODS: A retrospective six-year review of all donor egg cycles where the eggs are supplied by an infertile donor trying to conceive herself was carried out. Salpingectomy for hydrosalpinx was performed prior to IVF-ET. RESULTS: Clinical and delivered pregnancy rates (PRs) following fresh ET were not significantly different in donors vs recipients (60.0%, 45.8% vs 56.8%, 50.8%). Implantation rates were 27.3% vs 32.6%. The respective implantation rates following frozen ET were 13.8% and 14.4%. CONCLUSIONS: In the background of salpingectomy for hydrosalpinges the much higher PRs in recipients vs donors is no longer seen. The trend for higher implantation rates in recipients (about 20%) following fresh but not frozen transfer could still reflect some adverse effect of the controlled ovarian hyperstimulation regimen in a minority of women.

Transforming growth factor beta production and responsiveness in normal human melanocytes and melanoma cells.

Previous studies have shown that some human melanoma cells express transforming growth factor beta (TGF-beta) mRNA and are growth inhibited by exogenous TGF-beta, suggesting a possible negative autocrine role for this melanoma-derived growth factor. To better understand the role of endogenous TGF-beta in the development of melanoma, we investigated patterns of TGF-beta protein production and responsiveness of human melanoma cells as compared to normal melanocytes. Both cultured melanoma cells and normal melanocytes secreted biologically inactive, latent TGF-beta protein which, upon acid treatment, became biologically active. In melanoma cells, TGF-beta production occurred constitutively, i.e., in the absence of exogenous polypeptide growth factors. By contrast, in melanocytes, TGF-beta production depended on stimulation by exogenous growth factors such as insulin-like growth factor I. Exogenous, bioactive TGF-beta 1 at picomolar concentrations inhibited tritiated thymidine uptake of normal melanocytes, whereas melanoma cells demonstrated various degrees of resistance to TGF-beta-induced inhibition of DNA synthesis. Five of six cell lines were less sensitive than any of the melanocyte lines tested, and one cell line was completely resistant to inhibitory effects of TGF-beta on DNA synthesis. In vivo selection of melanoma cells for metastatic ability in athymic mice produced a variant cell line that was resistant to TGF-beta 1-induced inhibition of DNA synthesis and proliferation. Development of TGF-beta resistance in the variant cell line was not associated with changes in TGF-beta cell surface binding. Stable transfection of melanocytes with a plasmid expressing the Simian Virus 40 large T-antigen rendered these cells resistant to growth inhibition by TGF-beta, suggesting that TGF-beta inhibits melanoma/melanocyte growth via interaction with Simian Virus 40 large T-antigen-responsive transcription elements.

Induction of metalloproteinase activity in human T-lymphocytes.

Matrix metalloproteinases are thought to play major roles in a wide array of normal and pathological processes. These proteinases are involved in the degradation of the extracellular matrix and are believed to facilitate the movement of cells from one site to another. In the current study, we examined the expression of the 92 kDa gelatinase activity (MMP-9) by the human T-lymphoma cell line, HSB. Proteinase activity was greatly elevated when cells were treated with TPA. This induction was initially observed at 6 h post-TPA treatment and continued to increase up to 48 h. Proteinase induction was inhibited by actinomycin D and cycloheximide, indicating that nascent RNA and protein synthesis were required. Staurosporine, an inhibitor of protein kinase C activity, suppressed the TPA-induction of gelatinase activity. Our results suggest that TPA induces the 92 kDa gelatinase activity by activating protein kinase C. TGF-beta also induced proteinase activity, although to a lesser extent than TPA. Several criteria indicate that this enzyme is a member of the family of matrix metalloproteinases: (1) this activity was inhibited by EDTA, 1,10-phenanthroline and TIMP; (2) this activity bound to a gelatin-agarose affinity resin; (3) it has a mass of approx. 92 kDa on SDS-polyacrylamide gels; (4) it cleaves gelatin and (5) the inducible proteinase cross reacts with antiserum to MMP-9.

Regulation of cytokine expression in macrophages and the Langerhans cell-like line XS52 by calcitonin gene-related peptide.

Calcitonin gene-related peptide (CGRP) inhibits antigen presentation by Langerhans cells (LC) and macrophages, and LC are anatomically associated with CGRP-containing epidermal nerves. To determine whether CGRP may produce some of its functional effects through regulation of cytokine expression, we utilized enzyme-linked immunosorbent assay (ELISA) of conditioned supernatants to examine production of interleukin (IL)-10 and IL-1 beta protein in the LC-like cell line XS52 as well as the reverse transcriptase-polymerase chain reaction (RT-PCR) to examine levels of mRNA for IL-10, IL-1 beta, and the 40-kDa subunit (p40) of IL-12. CGRP augmented the lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF) -induced release of IL-10 protein and the induced expression of IL-10 mRNA in these cells. However, it suppressed the induction of release of IL-1 beta protein and the induction of mRNA for IL-12 p40 and IL-1 beta by LPS and GM-CSF. Regulation of cytokine expression in peritoneal macrophages was also examined. By ELISA, the LPS-induced expression of IL-10 was augmented by CGRP, whereas the induction of IL-1 beta was suppressed. Northern analysis demonstrated augmentation of LPS-induced IL-10 mRNA levels and inhibition of LPS-induced IL-1 beta mRNA by CGRP. CGRP inhibited the LPS-induced induction of IL-12 mRNA as assessed by RT-PCR. Up-regulation of B7-2 expression by LPS and GM-CSF was suppressed by CGRP in both XS52 cells and macrophages, as previously reported. This suppression, however, could be abrogated by co-culture with neutralizing antibodies to IL-10. Furthermore, the presence of neutralizing antibodies to IL-10 during exposure of epidermal cells (EC) to CGRP prevented the CGRP-mediated suppression of EC presentation of tumor-associated antigens (from the S1509a spindle cell carcinoma) for elicitation of delayed-type hypersensitivity in S1509a-immune mice. These data suggest that suppression of antigen-presenting function by CGRP is mediated, at least in part, by changes in cytokine expression that favor less robust antigen presentation for cell-mediated immunity.

Photoactivated hypericin is an anti-proliferative agent that induces a high rate of apoptotic death of normal, transformed, and malignant T lymphocytes: implications for the treatment of cutaneous lymphoproliferative and inflammatory disorders.

Hypericin is a photodynamic compound activated by either visible (400-700 nm) or UVA (320-400 nm) light, and has been shown to inhibit the growth of a variety of neoplastic cell types. In this study, hypericin was found to inhibit proliferative responses of malignant T cells derived from the blood of patients with cutaneous T cell lymphoma. Control cells included peripheral blood mononuclear cells (PBMC) from normal volunteers or Epstein-Barr virus-transformed lymphocytes. Cells from each of these populations were incubated with serial dilutions of hypericin or 8-methoxypsoralen and then stimulated with the mitogen ConA (10 microg per ml). Cultures were prepared in the dark to minimize photoactivation of the hypericin. Proliferation was measured by [3H]thymidine labeling after 72 h. Hypericin, photoactivated with 1.1-3.3 J white light per cm2, inhibited cellular proliferation of malignant T cells with IC50 values from 0.34 to 0.53 microM, normal PBMC with IC50 values of 0.11-0.76 microM, and Epstein-Barr virus-transformed cells with IC50 values of 0.75-3.2 microM. UVA-photoactivated hypericin (0.5-2.0 J per cm2) could also inhibit proliferation with IC50 values of 0.57-1.8 microM, 0.7-4.6 microM, and 2.0-3.7 microM for malignant, normal, or Epstein-Barr virus-transformed cells, respectively. Hypericin, photoactivated with either UVA or white light, could induce near complete apoptosis (94%) in malignant cutaneous T cell lymphoma T cells, whereas lower levels of apoptosis (37-88%) were induced in normal PBMC. These data indicate that hypericin inhibits mitogen-induced proliferation of malignant T cells from patients with cutaneous T cell lymphoma, PBMC from normal individuals, as well as Epstein-Barr virus-transformed lymphocytes, and that inhibition of cell proliferation is dependent on the concentration of hypericin used and the dose of light required to photoactivate the compound. Induction of apoptosis is, in part, one mechanism by which photoactivated hypericin inhibits malignant T cell proliferation.

Calcitonin gene-related peptide inhibits proliferation and antigen presentation by human peripheral blood mononuclear cells: effects on B7, interleukin 10, and interleukin 12.

CGRP is a neuropeptide that has previously been described to possess immunosuppressive activities. CGRP is released from peripheral nerves that, in the skin, are in close physical association with dendritic APC. We sought to investigate the mechanisms by which CGRP can inhibit immune responses by studying its effects on human peripheral blood mononuclear cells (PBMC). Using allogeneic monocytes as stimulator cells, CGRP could inhibit the proliferation of PBMC by 47% when CGRP was present for the duration of culture. Interestingly, when the stimulator monocytes were incubated with CGRP for 2 h prior to irradiation then washed, the observed inhibition increased to 85%, suggesting that CGRP was exerting a direct effect on the monocyte stimulator population. Finally, the recall response to tetanus toxoid (TT) by PBMC from individuals vaccinated with TT 14 d prior was inhibited by 25-50% in the presence of CGRP. Also, CGRP decreased the levels of B7.2 but not B7.1 on treated monocytes, and this inhibition could be abrogated by the addition of anti-IL-10 antibody, suggesting that the inhibition was mediated by an increase in IL-10 production. Moreover, increased IL-10 production was confirmed by ELISA. Both IL-12 p40 and IFN-gamma levels in CGRP-treated cultures were found to be decreased by approximately 30%. The decrease in IL-12 p40 levels could be reversed by addition of anti-IL-10. These data suggest that CGRP inhibits PBMC proliferation, in part, through the release of IL-10, which in turn can downregulate important co-stimulatory molecules and the cytokines IL-12 and IFN-gamma.

Retinoids synergize with interleukin-2 to augment IFN-gamma and interleukin-12 production by human peripheral blood mononuclear cells.

We have demonstrated previously that cells from both the skin and peripheral blood from patients with cutaneous T cell lymphoma (CTCL) have elevated levels of protein and mRNA for Th2 cytokines, interleukin-4 (IL-4) and IL-5, and depressed levels of Thl cytokines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, IL-12 in vitro can restore IFN-gamma production by these patients' cells to near normal levels. Because retinoids exert therapeutic activity in CTCL and are potent modulators of growth and differentiation of hematopoietic cells, we investigated the role of retinoids in modulating Thl cytokine production. Peripheral blood mononuclear cells (PBMC) from normal donors and patients with CTCL were cultured with medium, IL-2, 13-cis-retinoic acid, all-trans-retinoic acid, acetretin or etretinate alone, or IL-2 plus the retinoids for 24 h, and levels of IFN-gamma were determined using ELISA. IL-2 or retinoids alone could induce low but significant levels of IFN-gamma. However, when IL-2 was cultured with each retinoid, a synergistic augmentation of IFN-gamma levels (4-fold to 90-fold) was observed except in the case of etretinate. All-trans-retinoic acid (ATRA) was the most potent IFN-y inducer. Similar studies performed using PBMC from CTCL patients indicated the IFN-gamma augmentation occurred but in a blunted manner. The IFN-y-inducing effect of ATRA and 13-cis-retinoic acid could be abrogated by addition of anti-IL-12 antibodies, suggesting that IL-12 plays a role in the synergistic upregulation of IFN-gamma. Using an IL-12 p40-specific radioimmunoassay (RIA), we confirmed the presence of IL-12 in IL-2 plus retinoid-treated culture supernatants. Purified monocytes cultured with IL-2 plus ATRA did not secrete IL-12. Only when monocytes were cocultured with lymphocytes was there an increase in IL-12 production, suggesting the involvement of a paracrine feedback loop requiring both monocytes and lymphocytes. These data suggest that retinoids can induce Th1 cytokines from normal and CTCL PBMC and that this induction may be mediated through IL-12 production.

Richter's syndrome associated with loss of response to transforming growth factor-beta.

A patient with chronic lymphocytic leukemia developed a large cell lymphoma apparently derived from the same neoplastic B-cell clone (Richter's syndrome). At the same time, mitogen-stimulated proliferation of the patient's circulating leukemic B-cells was no longer inhibited by the regulatory cytokine transforming growth factor-beta (TGF-beta), suggesting that such loss of inhibition might be contributing to the clinical and biological progression of the disease.

The potential therapeutic role of interleukin-12 in cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a lymphoproliferative disorder characterized by skin invasion of clonally derived malignant CD4+ lymphocytes that phenotypically resemble mature T-helper (Th) cells. Sezary syndrome (SzS) represents an advanced form of CTCL associated with generalized erythroderma and involvement of the peripheral blood by the malignant cell population. We have previously demonstrated aberrant cytokine production by peripheral blood mononuclear cells (PBMCs) in SzS characterized by increased IL-4 and deficient IL-2 and IFN-gamma production, as well as increased expression of mRNA for IL-4 and IL-5 within active skin lesions, indicating that the clonal T-cell population is likely derived from the T-helper type 2 (Th2) subset of helper T lymphocytes. Furthermore, a variety of immune abnormalities have been observed in association with SzS that have been attributed to the cytokine abnormalities. Because IL-12 is a potent inducer of IFN-gamma production and causes the activation of cytotoxic lymphocytes, we assessed the production of IL-12 by PBMCs from SzS patients, and whether IL-12 could alter the unfavorable cytokine balance typical of SzS and, thus, possibly lead to correction of immune defects. In this review, we present our data, which indicate that patients with SzS exhibit marked defects in monocyte production of IL-12 p70. Moreover, in vitro culture of PBMC from SzS patients with recombinant IL-12 leads to reconstitution of normal IFN-gamma production and markedly enhances cell-mediated cytotoxicity.

Regulation of natural killer cytotoxicity by recombinant alpha interferons. Augmentation by IFN-alpha 7, an interferon similar to IFN-alpha J.

The structure-function relationship of several recombinant human alpha interferons (IFN-alpha) (IFN-alpha 1, IFN-alpha 2, IFN-alpha 4, IFN-alpha 7, IFN-alpha 2/alpha 1 and IFN-delta 4 alpha 1) was investigated with respect to their ability to augment natural killer (NK) cytotoxicity of human peripheral blood mononuclear cells (PBMC) against hemopoietic tumor cell lines. Although all these IFNs significantly augmented NK cytotoxicity against the K562, Daudi and U937 targets, significant quantitave differences were observed in their ability to augment NK. INF-alpha 4, IFN-alpha 2 and IFN-alpha 2/alpha 1 were able to augment NK at low concentrations (less than 0.1 ng/ml), whereas IFN-alpha 7, IFN-alpha 1 and IFN-delta 4 alpha 1 required significantly higher concentrations (3 ng/ml or higher). The cumulative rank order of INFs on the basis of NK augmenting ability was found to be: IFN-alpha 4 approximately IFN-alpha 2 approximately IFN-alpha 2/alpha 1 greater than IFN-alpha 7 greater than IFN-alpha 1 approximately IFN-delta 4 alpha 1. To determine synergism or potentiation in the ability of IFNs to augment NK cytotoxicity, we investigated the effect of simultaneous, sequential and reversed order of treatment of human PBMC by these IFNs. Such potentiation or synergism was not observed. In addition, all these IFNs were able to augment NK cytotoxicity against targets from malignant melanoma cell lines. IFN-alpha 7 augmented regularly and reproducibly NK cytotoxicity in 15 of 19 normal donors examined (79%). This augmentation was blocked by an anti-IFN-alpha antibody. Concentrations of IFN-alpha 7 as low as 0.06 ng/ml were able significantly to augment NK cytotoxicity of PBMC after incubation for one hour at 37 degrees C. In contrast to these findings, IFN-alpha J, an interferon similar to IFN-alpha 7, has been report to be incapable of augmenting NK cytotoxicity and also of interfering with augmentation of NK by other IFNs. Sequential treatment of PBMC first with IFN-alpha 7 and then with other interferons did not prevent the augmentation of NK. Similarly, simultaneous treatment with IFN-alpha 7 and other interferons did not prevent augmentation of NK. In both treatments IFN-alpha J has been reported to prevent augmentation of NK. IFN alpha J and IFN-alpha 7 differ only by one amino acid, at position 107, where a lysine in IFN-alpha J has been replaced by a glutamic acid in the IFN-alpha 7.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiation damage due to knock-on processes on carbon foils cooled to liquid helium temperature.

Radiation damage on a holey carbon foil was investigated in an electron microscope with a superconducting lens system, where the temperature of the specimen and its environment initially was 4 K. Due to an electron dose of 2 X 10(4) As/cm2 the diameter of a hole increased 5 nm. Rough calculations show that this increase can be ascribed to knock-on processes. Estimates of the rise in specimen temperature during the irradiation are given.

Improvements in electron microscopy by application of superconductivity.

Resolution tests on amorphous carbon foils were carried out in an electron microscope with a superconducting system containing 4 lenses including a shielding lens at 200 kV beam voltage. Due to the mechanical and electrical stability of the system and the absence of contamination of the specimen the highest space frequencies transferred at vertically incident beam were 6 nm-1 corresponding to a resolution of 0.17 nm, a value which approaches the theoretical resolving power of the electron optical system. It should also be feasible to apply such a lens system for microprobe analysis without strongly reducing the theoretical resolution limit, if the construction of the shielding lens is slightly changed.

Assessment of resident physicians' knowledge of physical therapy.

Half of all US medical schools offer courses in rehabilitation medicine; however, 46 states require physician referrals for physical therapy services. The purpose of this study was to identify areas of deficit in resident physicians' knowledge of selected physical therapy modalities and evaluative procedures and to determine if resident physicians perceived themselves to have adequate background to refer patients to physical therapy effectively. We mailed a questionnaire to 345 resident physicians chosen from area hospitals and obtained a response rate of 32 percent. The demographic portion of the questionnaire was analyzed by the use of descriptive and chi-square statistics. We tested knowledge of modalities and evaluative procedures through matching of treatment referrals with specific patient diagnoses and analyzed the data in terms of chi-square, frequencies, and correlated statistics. The results indicated that the majority of respondents refer patients to physical therapy (98%) and feel adequately informed to do so (54%). Test results, however, ranged from 1 to 73 percent correct, with only one score above 70 percent correct. This finding indicated a deficit in resident physicians' knowledge of physical therapy. We also identified a need for physical therapists to educate physicians about treatment modalities and evaluative procedures through continuing education programs.

Geriatric emergency clinical pharmacology.

Drugs associated with elderly individuals seen in the Emergency Department must be understood both as causal or etiologic agents of certain common presentations and as therapeutic tools. Special problems of the elderly include their increased frequency and altered patterns of drug use as compared with younger persons. They are predisposed to problems with certain drugs because of altered hepatic blood flow, renal clearance, body composition, sensitivities, and compliance that result from age. Most important, the practitioner is now provided with a set of resources, including lists of common presentations in the Emergency Department and specific drugs that must be considered to be potential etiologic or causative agents for that presentation. In addition, therapeutic agents for both physicians and elderly patients are presented in catechism.

Inhibition of interleukin 2 production and alteration of interleukin 2 mRNA processing by human T-T cell hybridoma-derived suppressor factors.

We investigated the mechanisms by which two human T-T cell hybridoma-derived suppressor factors (SFs) (designated 160 and 169) (Platsoucas et al., Hybridoma 1987;6:589; Kunicka et al., Hybridoma 1989;8:127) inhibit the proliferative response to mitogens by human peripheral blood mononuclear cells (PBMCs). Interleukin 2 (IL-2) production by human PBMCs cultured with concanavalin A or OKT3 monoclonal antibody for 12 or 36 hr in the presence of 160 or 169 SF was found to be inhibited > 80% when compared to control PBMC cultures stimulated with mitogen in the absence of SFs. This suppression of IL-2 production was not due to the SFs interfering with IL-2-induced proliferation of the IL-2-dependent murine cell clone used to determine the levels of IL-2. The proliferative responses of SF-treated PBMCs could not be restored by addition of exogenous recombinant human IL-2 (rIL-2) (1-100 U/ml). Furthermore, inhibition of the proliferative responses by the SFs could not be reversed by addition of exogenous rIL-1, rIL-2, or rIL-4 alone or in paired combinations. The expression of IL-2 receptors (TAC Ag) on concanavalin A-activated cultures at 12- or 36-hr time points was not affected by treatment with the SFs. Both the 160 and 169 hybridoma-derived SFs were found to cause the accumulation of an mRNA of 2.8 kb that hybridized with an IL-2-specific oligonucleotide probe. This 2.8-kb transcript was in addition to the expected 1.0-kb, transiently expressed IL-2 message, and it could be superinduced in the presence of cycloheximide. These results suggest that these SFs may be influencing RNA splicing pathways. These SFs appear to be useful molecules for probing the regulatory controls of lymphocyte proliferation and may constitute important physiological regulators of the immune response. In addition, they may have clinical activity for the treatment of patients that received transplants, patients with autoimmune diseases, and others.