Modulating co-stimulation

The modulation of co-stimulatory pathways represents a novel therapeutic strategy to regulate autoimmune diseases. Auto-reactive CD4+ T cells play a critical role in initiating the immune response leading to inflammation and autoimmune diseases. Blocking co-stimulatory signals prevents T-cell activation, thus diminishing autoimmune responses and possibly preventing the progression of autoimmune disease. Blockade of several co-stimulatory pathways has been investigated in animal models and has led to clinical trials testing specific blocking agents in humans. In this review we will describe the role of co-stimulatory pathways, primarily the CD28-B7 pathway, in autoimmune diseases, and we will present in vivo and in vitro studies supporting the efficacy of co-stimulation blockade in animal models of autoimmune disease. Finally, we will discuss the clinical therapeutic efficacy of blocking monoclonal antibodies in preventing or reducing auto-antigen driven T-cell activation in humans with particular attention to the CD28/B7 pathway. Inhibiting co-stimulatory molecule interactions by using monoclonal antibodies seems to be an original approach to regulate autoimmune diseases in humans.     

Characteristics of patients with congenital clasped thumb: a prospective study of 40 patients with the results of treatment

Purpose  Congenital clasped thumb is a deformity that is associated with heterogeneous congenital anomalies and it has been addressed in many congenital syndromes. The aim of this study was to diagnose and evaluate cases of clasped thumb as regards the associated congenital anomalies and syndromes, and evaluation of the results of treatment of such cases. Methods  A prospective study on 40 patients with 73 clasped thumbs was done. All the patients’ data regarding their personal, family, pregnancy and developmental histories were recorded. All the patients were exposed to thorough clinical and radiological examination and genetic assessment. The cases were classified using the Tsuyuguchi et al. (J Hand Surg [Am] 10:613–618, 1985) classification into three types. Conservative treatment was adopted in ten hands, and surgical treatment was performed for 28 hands in 17 patients, with an average follow-up of 26 months. Results  Positive consanguinity was recorded in 57.5% of cases. Associated anomalies were recorded in 77.5% of cases. Type I was the most common one, followed by type III and then type II. Conservative treatment is effective in type I cases when presented early, and all patients were satisfied with the results of surgical treatment. Conclusions  We reported associated anomalies which are to our knowledge have not mentioned before in the literature which include; congenital blindness, radial deviation of the index finger and ventricular septal defect. We found that 68% of the patients had associated syndromes, and this has not been mentioned before. In this study, we found that there were no difference between type II and type III clasped thumb as regards the pathological findings, severity, the operative procedures, the treatment protocol and the operative results. Properly planned treatment gives satisfactory results.     

Respiratory health status in swine producers using respiratory protective devices

A cross-sectional survey on respiratory health in swine producers showed that 30% of 301 examined men usually used a dust mask when working inside a barn. They did not differ significantly from dust mask nonusers in respect to respiratory symptoms and lung function. This analysis was undertaken to determine whether the respiratory health of dust mask users was associated with reasons why they had started individual respiratory protection. The subjects were recontacted in order to identify those who started using a mask to deliberately prevent symptoms (42 men) and those who started protection because of pre-existing respiratory symptoms (44 men). Not unexpectedly, betweengroup comparisons of respiratory symptoms and lung function suggest that swine producers who wear dust masks for preventive purposes have better respiratory health than those who wear dust masks because of symptoms or those who do not use individual respiratory protection. The individual reasons for starting dust mask usage should be examined among potential determinants of the outcomes of prospective studies which can then provide more valid assessment of the effect of individual respiratory protection. © 1993 Wiley-Liss, Inc.     

Non-secretion of ABO blood group antigens as a host susceptibility factor in the spondyloarthropathies

Gram negative bacteria precipitate reactive arthritis and may be concerned in the pathogenesis of ankylosing spondylitis and other spondyloarthropathies. Susceptibility to many infectious agents is associated with ABO blood group or secretor state, or both. The distribution of the ABO blood group or secretor state, or both, was therefore determined in 87 patients with ankylosing spondylitis and 32 with other forms of spondyloarthropathy. The prevalence of non-secretors was significantly increased in the total patient group (54/114; 47%) and in the subgroup with ankylosing spondylitis (41/84; 49%) compared with local controls (89/334; 27%) (p less than 0.001). Other subgroups of patients showed a similarly increased prevalence of non-secretion (33-47%). The distribution of ABO blood groups did not differ between patients and controls. The association between non-secretor state and ankylosing spondylitis strengthens the hypothesis that ankylosing spondylitis is a form of reactive arthritis. It also suggests several pathogenic mechanisms which may be relevant to the initial hostparasite interaction in ankylosing spondylitis.     

Functional and structural characteristics of the glycosaminoglycans of the bladder luminal surface

The glycosaminoglycan layer of bladder has been proposed to play a crucial role in protecting the bladder from harmful substances in urine. Rats were partially cystectomized to determine whether bladder glycosaminoglycans are routinely eluted from the bladder surface in detectable quantities. Cystectomy produced no detectable qualitative or quantitative changes in excreted GAG thereby showing that most urinary glycosaminoglycan originates in the kidney and not from the bladder. Damaging the glycosaminoglycan layer by a dilute acid wash, however, leads to a consistent decrease in the output of urinary GAG which recovers to normal at the same rate as the layer regenerates. This suggests that the newly exposed sites tightly bind urinary GAG. We suggest that such binding may be a component of the normal physiological defense mechanism of the bladder. The bladder glycosaminoglycan layer was isolated, dilute acid being used to elute ionically-bound material and brief trypsinization to elute intercalated proteoglycans from the luminal surface. The GAG from the luminal surface, which was present at a density of one chain per 50 nm.2 of bladder surface, was quite different in composition from that isolated from the whole bladder.     

Use of superparamagnetic contrast media to suppress signal from flowing spins: Preliminary experience

The authors describe their preliminary experience with the use of superparamagnetic magnetic resonance (MR) imaging contrast media for suppression of signal from flowing blood. The goal of this work was to determine if a superparamagnetic contrast agent could successfully eliminate blood signal during cardiac-gated MR imaging, thereby eliminating or reducing flow artifacts associated with the complex and variable hemodynamics within the heart chambers. Imaging and data analysis were performed in 17 dogs subjected to experimental myocardial infarction as part of a parallel project. Six doses (0.2, 1, 2, 3.5, 4, 5, and 10 mg/kg) of AMI-25, an experimental contrast agent, were used in the study. Spin-echo imaging was performed immediately before and every 5 minutes (for an average of 25 minutes) after bolus injection of the contrast agent. Variations in the image signal-to-noise ratio relative to a baseline (before injection of contrast agent) image were assessed as a function of dose and time. Preliminary results suggest that a considerable reduction in blood flow artifacts and, hence, increases in image signal-tonoise ratio can be achieved at doses greater than or equal to 3.5 mg/kg, for approximately 20 minutes after injection. Doses equal to or less than 2 mg/kg and images obtained more than 20 minutes after injection (regardless of dose) did not reliably show hemodynamic artifact suppression.     

Analysis of magnetization transfer effects on T1-weighted spin-echo scans using a simple tissue phantom simulating gadolinium-enhanced brain lesions

The purpose of this study was to analyze the effect of several magnetization transfer (MT) pulse and T1-weighted spin-echo (SE) sequence parameters on lesion-to-background contrast, using a simple tissue phantom emulating the T1 relaxation and MT properties of gadolinium-enhanced brain lesions. Eggbeaters (Nabisco Inc., East Hanover, NJ) liquid egg product was doped with gadolinium in six concentrations from .0 to 1.0 mmol and cooked. The gadolinium-doped egg phantom and normal volunteer brains were studied using an SE sequence with TE = 20 msec and high power, pulsed, off-resonance MT saturation. The effects of MT pulse frequency offset (1,000–6,000 Hz), sequence repetition time (TR = 500–1,000 msec, with MT power held constant), and slice-select flip angle (60–120 degrees) on the magnetization transfer ratio (MTR) and the simulated lesion-to-background contrast were determined at the different “Intralesion” gadolinium concentrations. The MTR and lesion-to-background contrast of all materials were greatest at narrow MT pulse frequency offsets. There was an inverse relationship between gadolinium concentration and MTR and a positive correlation between the gadolinium concentration and lesion-to-background (L/B) contrast, a weak negative correlation between slice-select flip angle and L/B, and a negative correlation between TR and L/B. The relaxation properties and MT behavior of the egg phantom are close to that expected for enhancing brain lesions, allowing a rigorous analysis of several variables affecting lesion-to-background contrast for high MT power, T1-weighted SE sequences.