Allogeneic CD3/CD28 cross-linked Th1 memory cells provide potent adjuvant effects for active immunotherapy of leukemia/lymphoma.

The breaking of peripheral T-cell tolerance toward self-antigens expressed by tumor cells and the subsequent establishment of an effective tumor protective immune response remains a major challenge for cancer immunotherapy. We report that both protective and therapeutic anti-tumor immune responses can be achieved in a mouse leukemia/lymphoma tumor model through the strong adjuvant effects provided by allogeneic CD3/CD28 cross-linked Th1 memory cells. The adjuvant effect of these cells is mediated by their ability to produce a variety of 'danger signals' which serve to deviate native non-protective Th2 anti-leukemia immune responses to effective Th1 immune responses.

Completely mismatched allogeneic CD3/CD28 cross-linked Th1 memory cells elicit anti-leukemia effects in unconditioned hosts without GVHD toxicity.

Fully allogeneic CD3/CD28 cross-linked Th1 cells were found to elicit host-mediated anti-leukemia effects without GVHD toxicity. Mice inoculated with a lethal dose of BCL1 leukemia demonstrated significantly enhanced survival after allogeneic Th1 treatment. Cure rates of 12.5% with a single allogeneic cell infusion and 31.25% with multiple infusions were demonstrated. Cured mice were able to reject rechallenge with a lethal dose of tumor without further treatment. These results suggest that use of intentionally mis-matched, Th1 memory cells infused with cross-linked CD3/CD28 could represent a novel clinical approach to eliciting potent anti-tumor effects in patients without conditioning and without GVHD toxicity.

Preliminary images from an adaptive imaging system.

I-ImaS (Intelligent Imaging Sensors) is a European project aiming to produce real-time adaptive X-ray imaging systems using Monolithic Active Pixel Sensors (MAPS) to create images with maximum diagnostic information within given dose constraints. Initial systems concentrate on mammography and cephalography. In our system, the exposure in each image region is optimised and the beam intensity is a function of tissue thickness and attenuation, and also of local physical and statistical parameters in the image. Using a linear array of detectors, the system will perform on-line analysis of the image during the scan, followed by optimisation of the X-ray intensity to obtain the maximum diagnostic information from the region of interest while minimising exposure of diagnostically less important regions. This paper presents preliminary images obtained with a small area CMOS detector developed for this application. Wedge systems were used to modulate the beam intensity during breast and dental imaging using suitable X-ray spectra. The sensitive imaging area of the sensor is 512 x 32 pixels 32 x 32 microm(2) in size. The sensors' X-ray sensitivity was increased by coupling to a structured CsI(Tl) scintillator. In order to develop the I-ImaS prototype, the on-line data analysis and data acquisition control are based on custom-developed electronics using multiple FPGAs. Images of both breast tissues and jaw samples were acquired and different exposure optimisation algorithms applied. Results are very promising since the average dose has been reduced to around 60% of the dose delivered by conventional imaging systems without decrease in the visibility of details.

The anti-tumor effect of allogeneic bone marrow/stem cell transplant without graft vs. host disease toxicity and without a matched donor requirement?

The anti-tumor immune response that occurs in allogeneic bone marrow/stem cell transplant (BMT) settings is capable of eradicating tumors that are resistant to chemotherapy/radiation treatment. This anti-tumor immune response, known as the graft vs. tumor (GVT) effect, is the most effective immunotherapy treatment ever discovered. Unfortunately, the clinical application of GVT is severely limited due to the intimate association of GVT with the extremely toxic and often lethal side-effect known as graft vs. host disease (GVHD). It is a major research focus in the field of BMT to develop methods to separate the beneficial GVT effect from the detrimental GVHD toxicity. However, due to the intimate association of these effects, attempts to limit GVHD also have a tendency to limit the GVT effect. We propose a new concept for harnessing the power of the GVT effect without the toxicity of GVHD. Rather than trying to separate GVT from GVHD, we propose that these naturally coupled effects can 'mirrored' onto the host immune system and maintain their intimate association. The 'mirror' of GVHD is a host rejection of a graft (HVG). As rejection of an allograft would not be toxic, an HVG effect coupled to a host vs. tumor (HVT) effect, the 'mirror' of the GVT effect, would provide the anti-tumor effect of BMT without GVHD toxicity. In the 'mirror' setting, the HVT effect must occur against syngeneic tumors, while in the BMT setting the GVT effect occurs in the allogeneic setting. Previous attempts to elicit syngeneic anti-tumor immunity using therapeutic tumor vaccines have had disappointing results in the clinic due to the influence of tumor immunoavoidance mechanisms. We propose that the 'danger' signals that are released as a result of GVHD in the allogeneic BMT setting serve as an adjuvant to the GVT effect disabling tumor immunoavoidance. The chemotherapy/radiation conditioning prior to transplant is a required initiating event to the coupled GVT/GVHD effects. The conditioning releases 'danger' signals that mediate this adjuvant effect. To imitate this immunological event in immunocompetent, non-conditioned patients we propose that infusion of freshly activated, polyclonal CD4+ memory Th1 cells which express CD40L on the cell surface will stimulate a HVT/HVG 'mirror' effect, providing a non-toxic means to elicit the effective immune-mediated anti-tumor effect of BMT without the GVHD toxicity and without the requirement for a matched donor.

The incidence of deep prosthetic infections in a specialist orthopaedic hospital: a 15-year prospective survey.

The Control of Infection Committee at a specialist orthopaedic hospital prospectively collected data on all episodes of bacteriologically-proven deep infection arising after primary hip and knee replacements over a 15-year period from 1987 to 2001. There were 10 735 patients who underwent primary hip or knee replacement. In 34 of 5947 hip replacements (0.57%) and 41 of 4788 knee replacements (0.86%) a deep infection developed. The most common infecting micro-organism was coagulase-negative staphylococcus, followed by Staphylococcus aureus, enterococci and streptococci. Of the infecting organisms, 72% were sensitive to routine prophylactic antimicrobial agents. Of the infections, 29% (22) arose in the first three months following surgery, 35% between three months and one year (26), and 36% (27) after one year. Most cases were detected early and treated aggressively, with eradication of the infection in 96% (72). There was no significant change in the infection rate or type of infecting micro-organism over the course of this study. These results set a benchmark, and importantly emphasise that only 64% of peri-prosthetic infections arise within one year of surgery. These results also illustrate the advantages of conducting joint replacement surgery in the isolation of a specialist hospital.

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice.

Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.

The outcome of perioperative wound infection after total hip and knee arthroplasty.

Forty-one consecutive patients with primary knee arthroplasty and 37 with primary hip arthroplasty, all with perioperative wound infections, were followed for 50 (12-130) months. Staphylococci (coagulase negative and positive) accounted for 74% of wound infections. Mixed organisms accounted for 10%. Prosthetic infections developed in eight patients and aseptic loosening in three patients. All the prosthetic infections developed within 6 months of the primary surgery. Organisms responsible for superficial infections were responsible for prosthetic infection in five patients; no organisms were isolated in the remaining three patients. The presence or absence of wound dehiscence, wound haematoma, and postoperative pyrexia did not predict the development of deep sepsis; however, the presence of wound discharge was a significant risk factor.

Carbapenem-resistant Acinetobacter and role of curtains in an outbreak in intensive care units.

Multiple-antibiotic-resistant Acinetobacter baumanii, including meropenem resistance, was first isolated from a patient in the general intensive care unit of a tertiary-referral university teaching hospital in Birmingham in December 1998. Similar strains were subsequently isolated from 12 other patients, including those on another intensive care unit within the hospital. The outbreak followed an increase in the use of meropenem in both the units. Environmental screening revealed the presence of the multiple-resistant Acinetobacter species on fomite surfaces in the intensive care unit and bed linen. The major source appeared to be the curtains surrounding patients' beds. Typing by pulsed field gel electrophoresis demonstrated that the patients' isolates and those from the environment were indistinguishable. Rigorous infection control measures including increased frequency of cleaning of the environment with hypochlorite (1000 ppm) and twice-weekly changing of curtains were implemented, along with restriction of meropenem use in the units. Isolation of the multiple-resistant Acinetobacter spp. subsequently diminished and it was not detected over a follow-up period of 18 months. To our knowledge, this is the first reported outbreak of carbapenem-resistant Acinetobacter spp. from the UK. This outbreak also highlights environmental sources, particularly dry fabrics such as curtains, as an important reservoir for dissemination of acinetobacters.

Food and microbiological problems in the newborn: data and practice.

We have reviewed the relationships of food, nutrition and feeding practices to various infections in the newborn. Tentative conclusions are made: (a) the initial use of human milk (raw or pasteurized) continues to offer advantages in the care of babies in intensive care; (b) attempts to mimic the microbiological effects of breast milk by manipulation of the composition of infant formulas have so far achieved little success, but this is a rapidly developing field; (c) we are wary of the widespread use of breast milk "fortifiers" until there is evidence that they do not adversely affect the protective properties of breast milk; (d) the doubtful advantages of nasojejunal feeding need to be weighed against the increased bacterial contamination of the upper small bowel; (e) systems monitoring in milk kitchens and the handling of feeds in the neonatal unit are an integral part of comprehensive neonatal care; (f) to limit nosocomial infection, particular attention to the faecal-food-oral route is necessary since there is potential for multiplication of initial contamination of food.

Methicillin resistant Staphylococcus aureus in milk.

Three separate outbreaks of gentamicin and methicillin resistant Staphylococcus aureus in a special care baby unit are described. The outbreaks ceased only after a milk bank worker was identified as a carrier of the strain. It is postulated that the infant milk feeds served as a vehicle of spread.

A comparison of pre-operative bathing with chlorhexidine-detergent and non-medicated soap in the prevention of wound infection.

In a 60-week cross-over study on 5536 patients in 20 wards of three city hospitals (two general and one orthopaedic), pre-operative bathing with chlorhexidine-detergent failed to influence the incidence of postoperative infection, in spite of the relatively high incidence of infection with skin organisms. Of the patients bathing pre-operatively with chlorhexidine-detergent, 5.4 per cent subsequently became infected (4.0 per cent of clean wounds) and of those bathing with unmedicated soap 4.9 per cent (3.5 per cent of clean wounds). A single pre-operative bath with chlorhexidine-detergent would, therefore, appear to be of dubious value in preventing postoperative wound infection.

Genital manifestation of filariasis.

The epidemiology, parasitology, and clinical and pathologic aspects of genital filariasis are reviewed. Emphasis is given to the milder forms of this disease which might be encountered in a routine urologic practice.