Evidence for the clonal abortion theory of B-lymphocyte tolerance

This paper deals with the behavior of adult mouse bone marrow cells placed in tissue culture with or without antigen, and subsequently assessed for immune competence after adoptive transfer into lethally X-irradiated, syngeneic hosts. Attention was focussed on B lymphocytes through using hapten human gamma globulin (HGG) preparations as putative tolerogens in tissue culture, the T-cell-independent antigens DNP-POL and NIP-POL as challenge injections in adoptive hosts, and numbers of hapten-specific PFC in host spleens for the quantitation of immune competence. It was found that the capacity of bone marrow cells to mount an adoptive immune response rose by a factor of about fivefold over 3 days in tissue culture. This rise was completely abolished by the presence in the culture of hapten-HGG conjugates with about one mole of hapten per carrier molecule. The prevention of the emergence of immune competence amongst maturing B cells was termed clonal abortion tolerogenesis. Dose-response studies showed the lowest effective antigen concentration to be between 2.5 times 10- minus 10 and 2.5 times 10- minus 9 M, and a standard concentration of 2.5 times 10- minus 8 M was chosen as producing near maximal effects. The tolerance was antigen-specific and time-dependent, being maximal only when antigen was present continuously as the cultured cells was maturing. It did not depend on the presence of T lymphocytes in marrow, and was not of an "infectious" type. In contrast to tolerogenesis of mature B lymphocytes by high antigen concentrations, it could not be abolished by lipopolysaccharide. We speculate that clonal abortion may be a tolerance mechanism of great physiological significance for self-recognition, and discuss the results in the framework of other recent tolerance models, including those involving receptor blockade and suppressor T cells.     

Development of novel amyloid imaging agents based upon thioflavin S

To date, small-molecule amyloid-imaging agents for in vivo detection and quantitation of amyloid deposits in Alzheimer's disease (AD) have been developed and successfully applied to human subjects. Preliminary studies have indicated that these amyloid-imaging agents were accumulated in the AD brains in a pattern that is relatively consistent with AD pathology, at least in the regions of amyloid-rich grey matter. These studies have also proven the concept that amyloid dyes, normally too hydrophilic to enter the brain, can be chemically modified to enhance brain permeability, binding affinity, as well as improve binding specificity for amyloid deposits. Related studies have suggested that structurally different agents can be developed that bind to different sites on amyloid deposits. In fact, in vivo cross-referencing studies based upon different amyloid-imaging agents may permit better characterization of AD pathology. But more importantly, novel amyloid imaging agents are required that will allow direct correlation between the results of animal models and human subjects based upon identical imaging modalities. Thus far, amyloid stains such as Congo red and thioflavin T have been extensively studied. However, another widely used amyloid dye, thioflavin S, has not been previously explored. This is in part due to the fact that thioflavin S exists as a mixture, not a pure chemical entity, albeit that the major component has been characterized. We hypothesized that neutral analogs, based upon the major component, could be developed as novel amyloid imaging agents, that exhibit complementary binding properties and pharmacokinetic profiles compatible with potential human studies.     

CT-guided suprascapular nerve blocks: a pilot study

Objective The objective of this study was to describe the suprascapular nerve block using CT guidance and to evaluate the short- and medium-term efficacy in a range of shoulder pathologies.Design and patients CT-guided infiltration around the suprascapular nerve was performed with bupivacaine and Celestone Chronodose on 40 consecutive patients presenting with chronic shoulder pathologies unresponsive to conventional treatment. Patients were interviewed using the Shoulder Pain and Disability Index (SPADI) before the procedure, 30 min after the procedure and at 3 days, 3 weeks and 6 weeks afterwards.Results Within 30 min of the block overall pain scores decreased from a mean (±SEM) pain score of 7.0 (±0.4) to 3.5 (±0.5) (n=39, P<0.001). At 3 days after the procedure, the mean overall improvement of the pain and disability scores were 20.4% (±4.9, P<0.001) and 16.8% (±4.8, P=0.004) respectively. Sustained pain relief and reduced disability were achieved in 10 of 35 (29%) patients at 3 weeks and longer. Patients suffering from soft tissue pathologies were the most likely patients to benefit from the injection. No serious side effects were noted.Conclusions In some patients with chronic soft tissue pathologies who do not respond to conventional treatment, a CT-guided suprascapular nerve block can provide safe short- and medium-term relief from pain and disability.     

The allelic spectra of common diseases may resemble the allelic spectrum of the full genome

Identification of the genes responsible for common human diseases promises to be one of the most significant advances in medical knowledge and treatment. To date, the numerous attempts to identify the genes responsible for complex and multi-factorial common diseases have met with only a handful of successes. The key to calculating the optimal effort and ideal approach to successful identifications lies with understanding the likely allelic spectrum of the target disease. The allelic spectrum describes the number of disease loci and the frequency of each disease allele. It has been implicitly assumed that disease spectra are biased towards either commonness or rareness relative to the allelic spectrum of the overall human genome. We present a hypothesis that the allelic spectra of common diseases are generally similar to the spectrum that characterizes the entire genome. This hypothesis is supported by the fact that only a few loci have major significance to familial disease risks and that there may be many disease loci which each make a minor contribution to a disease. Additionally, although relatively few alleles of the human genome have been examined for disease involvement, current estimates of the number of disease genes are very high. Because selection will have been operating only weakly and for a relatively short time on most of the alleles associated with complex diseases, spectra that are characteristic of near-neutral selection may well apply. We thus propose that the hitherto neglected hypothesis that puts the likely allelic spectra of common diseases in the middle ground between the prevailing hypotheses of spectral skew towards rareness or commonness is the most likely. By using this hypothesis as the null, research resources may be optimally allocated and greater success in identifying disease genes may be achieved.     

Radial nerve palsy owing to localized hypertrophic neuropathy (intraneural perineurioma) in early childhood

Localized hypertrophic neuropathy, also termed intraneural perineurioma, is a rare disorder of unknown etiology that produces a slowly progressive painless focal lesion of a peripheral nerve. It is characterized histologically by concentric whorls ("onion bulbs") of epithelial membrane antigen-reactive, S-100 protein-negative perineurial cells surrounding nerve fibers. We report a radial nerve palsy in a child aged 2 years in whom the diagnosis of localized hypertrophic neuropathy was made by biopsy. Resection of the affected nerve segment and sural nerve grafting produced no useful recovery after 3 years, probably because of the long duration of denervation. When this mononeuropathy presents in early childhood, uncertainty over the time of onset can lead to difficulty in distinguishing this potentially treatable lesion from congenital and other causes of nerve palsy.     

A cohort study of neurodevelopmental outcome in children with DiGeorge syndrome following cardiac surgery

Aims: To examine whether the learning difficulties seen in a proportion of children with DGS are secondary to cardiac pathology and treatment, or a feature of the DGS phenotype. Methods: Cohort study of all patients with DGS and coexisting cardiac lesions within a region. Ten children with 22q11 deletion were assigned two controls each, matched for age, sex, cardiac lesion, and preoperative hemodynamic status but without DGS. The neurodevelopmental status was evaluated with the Ruth Griffiths test for babies and young children. Results: Children with the 22q11 deletion showed a wide range of developmental quotient (DQ; mean 71, 95% CI 47 to 95) and subscale scores, but these as a group were significantly lower than those of the control group (DQ 113, 95% CI 108 to 118). Four of the DGS children had DQs below 60. Hypocalcaemia, prolonged postoperative ventilation, and abnormal neurology perioperatively were associated with a low DQ. Conclusions: A proportion of children with DGS have a very poor developmental outcome following cardiac surgery. This outcome is not attributable to the cardiac condition and its treatment alone, but represents either a pre-existing component of the syndrome or an interaction between the syndrome and its treatment.