Siemens Reloaded: Chloride-Assisted Selective Hydrodechlorination of SiCl4 to HSiCl3.

Trichlorosilane is the key intermediate for the large-scale production of polycrystalline silicon in the Siemens and Union Carbide processes. Both processes, however, are highly inefficient, and over two thirds of the trichlorosilane employed is converted to unwanted silicon tetrachloride accumulating in millions of tons per year on a global scale. In this combined experimental and theoretical study we report an energetically and environmentally benign synthetic protocol for the highly selective conversion of SiCl4 to HSiCl3 using organohydridosilanes as recyclable hydrogen transfer reagents in combination with onium chlorides as efficient catalysts. We put the same protocol to further use demonstrating the quantitative conversion of higher oligosilane residues, which form as another unwanted and potentially hazardous byproduct of Siemens processes, to HSiCl3 in a low-temperature recycling step.

1946 and the Early History of Hydrosilylation.

Three events occurred in the second half of 1946 in three adjoining US States (NJ, NY, and PA) which marked the birth of Hydrosilylation Technology. They occurred before the landmark 1957 JACS paper and the 1958 issued US patent by Speier et al. and before Chalk and Harrod named the reaction. First, on 27 June 1946, Mackenzie et al., of Montclair Research Corp., applied for a patent to prepare addition compounds of hydridosilanes and unsaturated organic compounds. Then, on 9 October 1946, Wagner and Strother of Union Carbide Corp. applied for a patent on a process to produce organic compounds of silicon with Si-C bonds by reacting a hydridosilane and an alkene or alkyne in the presence of a catalyst metal of the platinum group. Finally, Sommer et al., submitted a paper on peroxide-catalyzed hydrosilylation to JACS on 17 December 1946. It was published in January 1947. The landmark patent interference § and priority § case law associated with the Mackenzie et al. and Wagner et al., applications is well known to patent attorneys. This presentation will retrace the origins of hydrosilylation and report events (1946-1960) in the history of the reaction that are most probably unknown to most authors and presenters of hydrosilylation investigations. George Wagner's contribution to the birth of this technology is also highlighted.

Disilane Cleavage with Selected Alkali and Alkaline Earth Metal Salts.

The industry-scale production of methylchloromonosilanes in the Müller-Rochow Direct Process is accompanied by the formation of a residue, the direct process residue (DPR), comprised of disilanes Men Si2 Cl6-n (n=1-6). Great research efforts have been devoted to the recycling of these disilanes into monosilanes to allow reintroduction into the siloxane production chain. In this work, disilane cleavage by using alkali and alkaline earth metal salts is reported. The reaction with metal hydrides, in particular lithium hydride (LiH), leads to efficient reduction of chlorine containing disilanes but also induces disproportionation into mono- and oligosilanes. Alkali and alkaline earth chlorides, formed in the course of the reduction, specifically induce disproportionation of highly chlorinated disilanes, whereas highly methylated disilanes (n>3) remain unreacted. Nearly quantitative DPR conversion into monosilanes was achieved by using concentrated HCl/ether solutions in the presence of lithium chloride.

Bone marrow-liver-thymus (BLT) immune humanized mice as a model to predict cytokine release syndrome.

Cytokine release syndrome (CRS) is a serious and potentially life-threatening complication that can be associated with biological drug products. In vitro assays or in vivo tests using nonhuman primates may fail to predict CRS due to species differences and the complexity of immune system. Therefore, model species that have human-specific immune components may improve the ability to identify CRS and enhance product safety. In this study we used bone marrow-liver-thymus (BLT) humanized mice to test muromonab (OKT3), an anti-CD3 antibody with a black box warning for CRS. Initially, we completed pilot and dose escalation studies with muromonab and showed that when the dose was increased sufficiently, BLT-humanized mice experienced serious adverse outcomes including moribundity. Full studies compared muromonab treatment with adalimumab, saline, and a group pretreated with methylprednisolone prior to muromonab. We evaluated immune cell activation using flow cytometry and cytokine expression using a custom 10-plex cytokine assay to assess levels of human TNF-α, IFN-γ, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A, IL12/23p40, and GM-CSF. Muromonab treated mice had significant increases in all cytokines tested with T-cell depletion and T-cell activation noted. Adalimumab (active) and saline (inactive) control groups did not demonstrate cytokine expression changes or alterations in T-cell numbers or activation. Further, pretreatment with methylprednisolone blunted or abrogated cytokine increases. This study demonstrates that BLT-humanized mice are capable of experiencing CRS, and could be used to screen biologics for this adverse event to enhance patient safety.

Making Use of the Direct Process Residue: Synthesis of Bifunctional Monosilanes.

The industrial production of monosilanes Men SiCl4-n (n=1-3) through the Müller-Rochow Direct Process generates disilanes Men Si2 Cl6-n (n=2-6) as unwanted byproducts ("Direct Process Residue", DPR) by the thousands of tons annually, large quantities of which are usually disposed of by incineration. Herein we report a surprisingly facile and highly effective protocol for conversion of the DPR: hydrogenation with complex metal hydrides followed by Si-Si bond cleavage with HCl/ether solutions gives (mostly bifunctional) monosilanes in excellent yields. Competing side reactions are efficiently suppressed by the appropriate choice of reaction conditions.

BLT-Immune Humanized Mice as a Model for Nivolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains.

Checkpoint inhibitors represent a new class of therapeutics in the treatment of cancer that has demonstrated remarkable clinical effectiveness. However, some patients have experienced serious immune-mediated adverse effects including pneumonitis, hepatitis, colitis, nephritis, dermatitis, encephalitis, and adrenal or pituitary insufficiency. These adverse events were not predicted by nonclinical studies. To determine if bone marrow-liver-thymus (BLT) immune humanized mice could demonstrate these adverse effects, we studied the effect of nivolumab on 2 strains of BLT-humanized mice, NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac (NOG) and NOD.Cg-Prkdcscid Il2rgtm1Sug Tg(SV40/HTLV-IL3, CSF2)10-7Jic/JicTac (NOG-EXL). Mice were treated with 2.5, 5.0, or 10.0 mg/kg nivolumab or saline twice weekly for 28 days. BLT-NOG mice had significantly reduced survival compared with BLT-NOG-EXL mice. In spite of the difference in survival, both BLT-humanized strains showed adverse reactions similar to those reported in humans, including pneumonitis and hepatitis, with nephritis, dermatitis and adrenalitis also noted in some individuals. Additional histopathologic findings included pancreatic atrophy, myositis, and osteomyelitis in some animals. T-cell activation increased with concomitant loss of PD-1 detection. These findings show that BLT immune humanized mice can demonstrate immune-mediated adverse effects of antiPD1 therapy, and may represent a model that can be used to better understand toxicity of this class of drugs.

Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20-Specific Cytotoxicity Induced by Ofatumumab.

CD20 monoclonal antibodies are well-established therapeutics for the treatment of B-cell malignancies. Several mechanisms of target cell killing occur from anti-CD20 therapy, including complement-dependent cytotoxicity (CDC) cell lysis and antibody-dependent cell-mediated cytotoxicity. Human Fc receptors (FcRs) are required to mediate these functions and are either not present or not cross-reactive in mice and most animal species. In contrast, some nonhuman primates have cross-reactive FcR; however, their cellular expression and function may differ from humans. Therefore, we tested bone marrow-liver-thymus (BLT) humanized mice to determine if they could recapitulate the pharmacokinetics (PKs), pharmacodynamics, and potential toxicities of ofatumumab, for which CDC is the predominant mechanism of action. Ofatumumab-treated BLT mice depleted B cells in a dose-dependent manner in all tissues sampled and recapitulated the PKs observed in humans, suggesting that BLT mice can mediate the CDC effector mechanism associated with biological drug products.

Synthesis of Functional Monosilanes by Disilane Cleavage with Phosphonium Chlorides.

The Müller-Rochow direct process (DP) for the large-scale production of methylchlorosilanes Men SiCl4-n (n=1-3) generates a disilane residue (Men Si2 Cl6-n , n=1-6, DPR) in thousands of tons annually. This report is on methylchlorodisilane cleavage reactions with use of phosphonium chlorides as the cleavage catalysts and reaction partners to preferably obtain bifunctional monosilanes Mex SiHy Clz (x=2, y=z=1; x,y=1, z=2; x=z=1, y=2). Product formation is controlled by the reaction temperature, the amount of phosphonium chloride employed, the choice of substituents at the phosphorus atom, and optionally by the presence of hydrogen chloride, dissolved in ethers, in the reaction mixture. Replacement of chloro by hydrido substituents at the disilane backbone strongly increases the overall efficiency of disilane cleavage, which allows nearly quantitative silane monomer formation under comparably moderate conditions. This efficient workup of the DPR thus not only increases the economic value of the DP, but also minimizes environmental pollution.

Bis(imino)pyridine cobalt-catalyzed dehydrogenative silylation of alkenes: scope, mechanism, and origins of selective allylsilane formation.

The aryl-substituted bis(imino)pyridine cobalt methyl complex, ((Mes)PDI)CoCH3 ((Mes)PDI = 2,6-(2,4,6-Me3C6H2-N═CMe)2C5H3N), promotes the catalytic dehydrogenative silylation of linear α-olefins to selectively form the corresponding allylsilanes with commercially relevant tertiary silanes such as (Me3SiO)2MeSiH and (EtO)3SiH. Dehydrogenative silylation of internal olefins such as cis- and trans-4-octene also exclusively produces the allylsilane with the silicon located at the terminus of the hydrocarbon chain, resulting in a highly selective base-metal-catalyzed method for the remote functionalization of C-H bonds with retention of unsaturation. The cobalt-catalyzed reactions also enable inexpensive α-olefins to serve as functional equivalents of the more valuable α, ω-dienes and offer a unique method for the cross-linking of silicone fluids with well-defined carbon spacers. Stoichiometric experiments and deuterium labeling studies support activation of the cobalt alkyl precursor to form a putative cobalt silyl, which undergoes 2,1-insertion of the alkene followed by selective ß-hydrogen elimination from the carbon distal from the large tertiary silyl group and accounts for the observed selectivity for allylsilane formation.

Iron catalysts for selective anti-Markovnikov alkene hydrosilylation using tertiary silanes.

Alkene hydrosilylation, the addition of a silicon hydride (Si-H) across a carbon-carbon double bond, is one of the largest-scale industrial applications of homogeneous catalysis and is used in the commercial production of numerous consumer goods. For decades, precious metals, principally compounds of platinum and rhodium, have been used as catalysts for this reaction class. Despite their widespread application, limitations such as high and volatile catalyst costs and competing side reactions have persisted. Here, we report that well-characterized molecular iron coordination compounds promote the selective anti-Markovnikov addition of sterically hindered, tertiary silanes to alkenes under mild conditions. These Earth-abundant base-metal catalysts, coordinated by optimized bis(imino)pyridine ligands, show promise for industrial application.

The acute effects of olive oil v. cream on postprandial thermogenesis and substrate oxidation in postmenopausal women.

The influence of the source of dietary fat on postprandial thermogenesis and substrate oxidation rates, was examined in twelve postmenopausal women aged 57-73 years, with BMI 21.9-38.3 kg/m(2). A single blind, randomised, paired comparison of two high-fat, isoenergetic, mixed test meals was conducted. The major source of fat was either cream (CREAM) or extra virgin olive oil (EVOO). RMR, diet-induced thermogenesis (DIT) and substrate oxidation rates over 5 h were measured by indirect calorimetry. There were no differences in body weight, RMR, fasting carbohydrate or fat oxidation rates between the two occasions. DIT (EVOO 97 (SD 46) v. CREAM 76 (SD 69) kJ/5 h and EVOO 5.2 (SD 2.5) v. CREAM 4.1 (SD 3.7)% energy) did not differ between the two test meals. The postprandial increase in carbohydrate oxidation rates, relative to their respective fasting values (DeltaCOX), was significantly lower following the EVOO meal (EVOO 10.6 (SD 8.3) v. CREAM 17.5 (SD 10) g/5 h; paired t test, P=0.023), while postprandial fat oxidation rates (DeltaFOX) were significantly higher (EVOO 0.0 (SD 4.4) v. CREAM -3.6 (sd 4.0) g/5 h; P=0.028). In the eight obese subjects, however, DIT was significantly higher following the EVOO meal (EVOO 5.1 (SD 2.0) v. CREAM 2.5 (sd 2.9) %; P=0.01). This was accompanied by a significantly lower DeltaCOX (EVOO 10.9 (SD 9.9) v. CREAM 17.3 (SD 10.5) g/5 h; P=0.03) and significantly higher DeltaFOX (EVOO 0.11 (SD 4.4) v. CREAM -4.1 (SD 4.5) g/5 h, P=0.034). The present study showed that olive oil significantly promoted postprandial fat oxidation and stimulated DIT in abdominally obese postmenopausal women.

Rolling circle amplification for scoring single nucleotide polymorphisms.

The analysis of the genetic basis of phenotypic traits is moving towards the complex diseases prevalent in wealthy populations. There is an increasing requirement for the detection of different types of sequence variation, particularly single-nucleotide polymorphisms (SNPs). SNPs occur about once every 100 to 300 bases. High-density SNP maps will help to identify the multiple genes associated with complex diseases such as cancer, diabetes, vascular disease, and some forms of mental illness.

Pain and powerlessness: the experience of living with peripheral vascular disease.

Peripheral vascular disease (PVD) is a widespread condition, the most common manifestation being a gradual occlusion of the arteries of the legs due to atheroma, which results in symptoms of ischaemia such as intermittent claudication or rest pain, ulceration and gangrene. Treatment of the condition is palliative and reconstructive, and aims to salvage the limb, restore mobility and function, and relieve pain. It usually involves attempts to revascularize the affected limb, either by surgical procedures such as bypass grafting, or by percutaneous transluminal angioplasty or thrombolysis. In some cases, it may be necessary to amputate the limb or part of it. Despite the chronicity of PVD, little is known about the ways in which individuals with vascular disease cope with their condition and about the effect it has on their life. In this context the aims of this study were to explore the lived experience of peripheral vascular disease, in order to identify key themes and categories, using a phenomenological grounded theory approach. A sample of nine individuals was drawn from patients who had had vascular bypass surgery within the past 18 months. Data were collected using audiotaped one-to-one interviews and the researcher's field notes, and were validated with a group of experienced vascular nurses. Transcripts were analysed using open and axial coding techniques, and major and minor categories were identified and related to other data collected. It appeared that vascular patients experienced powerlessness in relation to the direct effects of their condition and in relation to its treatment modalities. The findings suggested that the 'acute' style of management of PVD often led to unrealistic expectations on the patient's part, which gave rise to the experience of powerlessness. The implications of these findings for the management of patients with PVD are discussed.

Nursing knowledge, theory and method revisited.

With the approach of the 21st century, nursing is having to respond to diverse influences which are remoulding the professional landscape. Not least of these is the changing status of western economies which underpins a drive towards evidence-based practice and an increased emphasis on multidisciplinary approaches to health care delivery. Certainty in health care is now a thing of the past. Central to the way the nursing profession embraces the future is its underlying philosophy: that which articulates professional values and shapes practice, research, education and management. In a time of change it is therefore essential to revisit the philosophical framework which underpins nursing. The debate in nursing research and theory appears to have stressed the polarization of viewpoints. It may be the case that feminist writers, ethnographers, positivist researchers and nursing theorists, in defending their own points of view, diminish rather than enhance professional dialogue. This paper reviews the nature of this debate within nursing and considers the implications that a dichotomous position may have for knowledge, theory and research method within the current context of health care. It then suggests a philosophical framework which could be relevant and accessible across the whole spectrum of nursing activity. In so doing, the paper aims to contribute to the discussion around epistemology and method in a way which encompasses the diversity found within the broad church of nursing.

A homogeneous method to quantify mRNA levels: a hybridization of RNase protection and scintillation proximity assay technologies.

A novel method to measure mRNA levels has been developed by combining the detection capabilities of RNase protection (RPA) with the quantification advantages of scintillation proximity assay (SPA) technology. Sample processing is reduced to the addition of a single reagent post RNase digestion. As a model system, the inducible expression of rat apolipoprotein-A1 mRNA has been measured by both traditional gel-based RPAs and the SPA-based RPA assay. Results demonstrate that the ribonuclease protection proximity assay (RiPPA) faithfully reproduces the gel-based results and is at least as sensitive as many existing methods.

The role of clinical directorate managers in facilitating evidence-based practice: a report of an exploratory study.

This paper presents an exploration of the role of clinical directorate managers in facilitating evidence-based practice. It reports on a small qualitative study which explored the perceptions held by directorate managers regarding their role in facilitating evidence-based practice for their nursing teams. Insights were sought into the nature of the overt and covert behaviours which the managers used in encouraging nurses to base their practices on research evidence. The sample consisted of 10 directorate managers from two teaching hospitals in one Trust, whose characteristics were not atypical from other directorate managers. Data were collected using semi-structured, tape-recorded interviews. Interviews focused on manager's backgrounds, professional responsibilities and practices, personal research agendas and socio-political influences. Findings revealed some constraining influences on the development of evidence-based practice, such as the Clinical Managers' budget allocations, and the policies and goals of the Trust. However, in respect of the managers' own practices, whilst some facilitative behaviours were identified, the data suggested that clinical managers were behaving in a manner which actually inhibited the development of evidence-based nursing practice. It would appear that in the post-reform National Health Service (NHS) clinical managers find themselves in a difficult position which gives rise to a practical failure to use their position and organizational authority to influence the utilization of research in practice. The implications of these findings for an evidence-based health service are discussed.

Nurses' attitudes toward computerization in clinical practice in a British general hospital.

The growth of information technology systems associated with the organizational reforms of the British Health Service has given rise to a need to understand nurses' attitudes toward computerization. Several studies in the United States have identified various factors that influence nurses' computer-related attitudes but such studies in the United Kingdom are rare. This study sampled 208 nurses in a general hospital of approximately 500 beds, and measured their computer-related attitudes using Stronge and Brodt's questionnaire. Demographic data specifically related to the UK scene also were collected. Although nurses' computer-related attitudes generally were positive, significant differences were found in relation to age, length of service as a trained nurse, job title, type of nursing unit, and length of service at the study hospital. Brodt and Stronge also found significant differences related to length of time as a trained nurse and nursing unit, but not for length of service or age. Discussion of the study findings suggests that the UK scene is not dissimilar to that in the United States. However, comparison of findings with Brodt and Stronge's work raises some questions about trends in nurses' computer-related attitudes and about the usefulness of computer technology to professional nursing practices.

Development of a high-volume in situ mRNA hybridization assay for the quantification of gene expression utilizing scintillating microplates.

A high-volume plate-based in situ hybridization assay has been developed, utilizing Amersham Cytostar-T scintillating microplates. This assay reliably detects specific mRNA transcripts at the level of 10-20 copies per cell. Radiolabeled antisense riboprobes specific for c-fos and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as well as nonhomologous vector-derived control probes were used to compare mRNA levels in quiesced rat A10 smooth muscle cells after stimulation with platelet-derived growth factor (PDGF). Maximal c-fos induction occurred following stimulation of A10 cells with 30 ng/ml of PDGF, corresponding to a signal from the c-fos probe of 700 cpm. The nonhomologous control background of 50 cpm and the GAPDH signals of 1700 cpm were independent of stimulation with PDGF or serum. Using PDGF, at 30 ng/ml, quiesced cells were stimulated at various times to provide an induction time course for c-fos mRNA which peaked at 30 min and returned to basal levels within 2 h. Comparison with parallel Northern blotting experiments showed this in situ assay to be at least 20-fold more sensitive and much more rapid to perform.

An exploration of the influence of managerial factors on research utilization in district nursing practice.

This paper reports a small study which explored the management arrangements of the providers of community services in five health districts and the influence these had on the way research findings were utilized by nurses in their clinical practice. Insights were sought into the nature of the organizations in which district nurses worked. With the co-operation of the service managers, all the nurses had previously been involved in testing a model of dissemination of research information. The study reported here arose from that original research and explored the links between management arrangements and research utilization in clinical practice. Interviews using a semi-structured schedule are reported from 22 service managers in the five health districts. Data on managers' professional roles and backgrounds, the organizational structures and processes and external social and political factors were collected and analysed. A selection of findings is discussed in relation to influence on research utilization in clinical practice.

Towards knowledge-based practice; an evaluation of a method of dissemination.

This paper describes a method for the dissemination of research-based information to nurses. The approach involved the development and evaluation of a clinical information pack relating to the management of leg ulcers. The evaluation incorporated a pre-post test two group experimental design. The sample comprised 171 qualified community nurses working in five health authorities. Data were collected by means of two extensive questionnaires administered to groups of nurses. The study collected large amounts of descriptive data pertaining to nurses' clinical practices in the care of this patient group. It also uncovered important factors, quite independent of leg ulcers, related to relationship between research and clinical practice, and the way information is disseminated to practitioners. These independent findings and their implications are discussed here.