Use of a Clostridium perfringens vector to express high levels of SIV p27 protein for the development of an oral SIV vaccine

Clostridium perfringens is a normal bacterial flora of the small and large intestines of humans and other animals. The current study investigates the potential use of a noncytotoxic C. perfringens as an oral vaccine vehicle for expression and intestinal delivery of a large amount of SIV antigens. Here we report the construction of a recombinant C. perfringens vaccine vector expressing high levels of SIV p27 during sporulation. Following oral administration of this recombinant C. perfringens vaccine vector to mice, large amounts of intact p27 protein were detected in the terminal ileum where the majority of Peyer's Patches (PPs) are located. Furthermore, dendritic cells (DCs) beneath the mucosal surface in the PPs were able to capture SIV p27 antigen, when PPs were exposed to C. perfringens expressing SIV p27 antigen. In addition, uptake of C. perfringens was able to induce maturation of mouse DCs. These results support the potential use of C. perfringens as an oral SIV/HIV vaccine vector.     

Current understanding of cellular and molecular events in intervertebral disc degeneration: implications for therapy

Until recently, material removed from the intervertebral disc (IVD) at surgery consisted either of 'loose bodies' from the centre of the IVD or discal tissue displaced (prolapsed) into the intervertebral root or spinal canals. This material is best regarded as a by-product of disc degeneration and therefore not representative of the disease process itself. Recent advances in surgical techniques, particularly anterior fusion, in which large segments of the anterior part of the IVD are excised with the anatomical relationships between different components intact, have generated material that can be investigated with modern molecular and cell biological techniques. This is an important area of study because degeneration of the lumbar IVDs is associated, perhaps causally, with low back pain, one of the most common and debilitating conditions in the West. 'Degeneration' carries implications of inevitable progression of wear-and-tear associated conditions. Modern research on human IVD tissue has shown that this is far from the case and that disruption of the micro-anatomy described as degeneration is an active process, regulated by locally produced molecules. The exciting consequence of this observation is the possibility of being able to inhibit or even reverse the processes of degeneration using targeted therapy.     

Dissociation and displacement: where goes the "ouch?"

Hypnosis is widely used to relieve pain. Current theory emphasizes its dissociative features. Multiple personality patients can eliminate pain in the primary personality by displacing it into underlying alters. The Hilgards demonstrated that normal hypnotized subjects can similarly dissociate pain into a covert cognitive structural system which they called the "hidden observer." The Watkins discovered that "hidden observers" appeared to be the same phenomenon as "ego states." "Ego-state theory" assumes that human personality develops through integration and differentiation. At one end of the continuum, "differentiation" is adaptive. Ego states possess relatively permeable boundaries as in normal moods. At the other end ego-state boundaries become less permeable. Normal "differentiation" becomes maladaptive "dissociation" and multiple personalities may be created. In the intermediate range of the differentiation/dissociation continuum, "covert" ego states can be found in many normal subjects who volunteer for hypnotic laboratory experiments. Normal individuals, like multiple personalities and "hidden observer" subjects, can displace (dissociate) pain into "covert" ego states. The pain is not eliminated. This suggests that when we remove pain by hypnosis we may not be getting away "scot-free."     

The barrier function of CYP3A4 and P-glycoprotein in the small bowel

CYP3A4 present in small bowel enterocytes can catalyze substantial metabolism of some orally administered drugs and, thus, exerts a first-pass effect. Recent data indicate that the P-glycoprotein (the MDR 1 gene product) in the enterocyte brush border also limits the bioavailability of many of the same drugs that interact with CYP3A. It has been proposed that P-glycoprotein and CYP3A4 may be functionally linked because (a) the two proteins are co-localized within the digestive tract and within enterocytes, (b) they share many of the same substrates and (c) they are co-inducible in response to at least some xenobiotics. There are several potential mechanisms whereby the functions of P-glycoprotein and CYP3A4 could be complimentary. First, Pgp may limit absorption in the proximal small bowel, shifting it to more distal, less catalytically efficient segments that contain lower amounts of CYP3A4. Second, Pgp may function to prolong the duration of absorption. This might increase the duration of exposure of drug to and, hence, the extent of metabolism by enterocyte CYP3A4. Finally, Pgp may preferentially remove from the enterocyte primary drug metabolites that are themselves substrates for CYP3A4. This would limit product inhibition and facilitate primary metabolism catalyzed by CYP3A4. Characterization of the roles of CYP3A4 and Pgp in limiting oral drug availability may be aided by recent success in the development of human intestinal cell lines that stably express both CYP3A4 and Pgp.     

An experimental investigation of the spray issued from a pMDI using laser diagnostic techniques.

This research was concerned with the experimental investigation of the spray issued from a pressurised metered-dose inhaler (pMDI) using laser diagnostic techniques and has been motivated by the urgent need to find suitable replacements to the environmentally destructive CFC propellants currently used in the device. The experimental work was conducted using phase-Doppler particle analysis (PDPA), a single particle light scattering technique that provides the simultaneous measurement of drop size, velocity, and concentration, yielding the most detailed temporal and spatial analysis of the pMDI spray to date. Three formulations were studied to compare the performance of an "ozone-friendly" hydrofluoroalkane propellant against that of a traditional CFC propellant mixture and a commercially available CFC formulation containing drug and surfactant. The PDPA analysis was complemented by a visual investigation of the near-orifice flow field using copper laserstrobe microcinematography to obtain information on the primary atomization process of the pMDI. This work was conducted in parallel with the theoretical investigation of the spray issued from a pMDI.     

Phase II study of intravenous melphalan (NSC-8806) in the treatment of patients with advanced squamous carcinoma of the head and neck

The Illinois Cancer Center entered 25 patients on a phase II trial of intravenous melphalan treating patients with recurrent, metastatic or locally advanced and inoperable squamous cell carcinoma of the head and neck. All patients had bi-dimensionally measurable disease, at least a sixty day life expectancy, and adequate performance status (ECOG scale 2). All patients except one had received prior radiotherapy, chemotherapy or both. Melphalan dosage was 30 mg/m² every three weeks. Twenty-four patients were evaluable for response. One patient with laryngeal carcinoma had a clinical complete response of a nodal metastasis. Four patients had stabilization of disease for one to three months. There was formidable toxicity, including neutropenia (ANC < 1000/l 36%), and thrombocytopenia (< 50,000/l 32%). There were no drug-related deaths. Melphalan administered intravenously does not appear to be efficacious therapy in patients with previously treated advanced head and neck squamous carcinomas.     

Stress-induced reduction in the rat mixed lymphocyte reaction is due to macrophages and not to changes in T cell phenotypes

Exposure to aversive events or Stressors modulates various aspects of immune function. We have previously reported that exposure to an acute Stressor, inescapable tail shock (IS), resulted in a shift in T cell subpopulations in rat mesenteric lymph nodes but not in cervical lymph nodes (Fleshner et al. (1992) J. Neuroimmunol. 41, 131–142). The mesenteric ratio was increased immediately after exposure to IS and was due primarily to an increase in the percent of CD4⁺ cells. The present experiments were designed to determine the relationship between the IS-associated phenotypic shift and its significance in the function of CD4⁺ T cells. The function assessed was the in vitro proliferative response to alloantigens coded for by the Major Histocompatibility Complex (MHC). Using the mixed lymphocyte reaction (MLR), we report that exposure to IS resulted in a decrease in the MLR response of cells from both cervical and mesenteric lymph nodes. Depletion of macrophages (nylon wool adherent cells) eliminated the IS-induced reduction and co-culture of macrophages (irradiation-insensitive cells) from shocked rats produced the suppression. One interpretation of these data is that exposure to IS resulted in the activation of macrophages and the release of a suppressive factor which reduced the MLR response of peripheral lymph node lymphocytes.     

Evaluation of a hospital picture archiving and communication system

OBJECTIVES: To establish the net costs to the hospital and the broad range of benefits associated with a hospital-wide picture archiving and communication system (PACS) that comprised digital acquisition, storage and transmission of radiological images via a hospital-wide network to 150 workstations. METHODS: 'Before and after' comparisons and time series analyses at Hammersmith Hospital (London, UK), and comparison with five other British hospitals where PACS was not being installed. The cost analysis considered implementation costs and changes in key elements of hospital running costs, including the impact of changes in the length of inpatient stays. A range of benefit measures were investigated, including image availability, avoidance of repeat imaging, avoidance of exposure to radiation, patient turn-round speed, time from examination to image availability in intensive care, avoidance of diagnostic 'errors' by casualty doctors, the additional diagnostic value of PACS-based images and clinician satisfaction. RESULTS: The annual equivalent capital cost of the PACS was 1.7 million Pounds (annual equivalent replacement cost: 0.8 million Pound). Overall, the PACS substantially increased running costs. No convincing evidence of a PACS-induced change in length of inpatient stay was found. PACS was associated with some improvements in the performance of the radiology department: improved image availability (97.7% versus 86.9%), lower repeat imaging rate (7.3% versus 9.9%) and 20% lower total radiation doses for examinations of the lateral lumbar spine. No improvements were identified in the quality of the radiology reporting service. Benefits outside radiology included shorter time from examination to image availability for routine uses in intensive care (19 versus 37 minutes), and a lower rate of diagnostic 'errors' in casualty (0.65% versus 1.51%). High levels of satisfaction with PACS were found amongst both providers and clinical users. CONCLUSIONS: PACS was almost universally preferred by users and brought many operational and clinical benefits. However, these advantages came at a significant capital and net running cost.