Antigen-specific regulatory T cells--their induction and role in infection

In addition to the well-established role of natural CD4(+)CD25(+) regulatory T (Tr) cells in the maintenance of tolerance to self-antigens, there is accumulating evidence for distinct populations of Tr cells induced in the periphery after encounter with pathogens and foreign antigens. These antigen-specific T cells, termed Tr1 or Th3 cells, secrete IL-10 and or TGF-beta, but no IL-4 and little or no IFN-gamma, and are induced by semi-mature dendritic cells under the influence of regulatory cytokines, including IL-10, TGF-beta and IL-4. Tr1 or Th3 cells are capable of suppressing Th1 and Th2 responses and function in infection to limit pathogen-induced immunopathology, but can also be exploited in therapies for immune-mediated diseases.     

Adenylate cyclase toxin from Bordetella pertussis synergizes with lipopolysaccharide to promote innate interleukin-10 production and enhances the induction of Th2 and regulatory T cells

Adenylate cyclase toxin (CyaA) from Bordetella pertussis can subvert host immune responses allowing bacterial colonization. Here we have examined its adjuvant and immunomodulatory properties and the possible contribution of lipopolysaccharide (LPS), known to be present in purified CyaA preparations. CyaA enhanced antigen-specific interleukin-5 (IL-5) and IL-10 production and immunoglobulin G1 antibodies to coadministered antigen in vivo. Antigen-specific CD4(+)-T-cell clones generated from mice immunized with antigen and CyaA had cytokine profiles characteristic of Th2 or type 1 regulatory T (Tr1) cells. Since innate immune cells direct the induction of T-cell subtypes, we examined the influence of CyaA on activation of dendritic cells (DC) and macrophages. CyaA significantly augmented LPS-induced IL-6 and IL-10 and inhibited LPS-driven tumor necrosis factor alpha and IL-12p70 production from bone marrow-derived DC and macrophages. CyaA also enhanced cell surface expression of CD80, CD86, and major histocompatibility class II on immature DC. The stimulatory activity of our CyaA preparation for IL-10 production and CD80, CD86, and major histocompatibility complex class II expression was attenuated following the addition of polymyxin B or with the use of DC from Toll-like receptor (TLR) 4-defective mice. However, treatment of DC with LPS alone at the concentration present in the CyaA preparation (0.2 ng/ml) failed to activate DC in vitro. Our findings demonstrate that activation of innate cells in vitro by CyaA is dependent on a second signal through a TLR and that CyaA can promote Th2/Tr1-cell responses by inhibiting IL-12 and promoting IL-10 production by DC and macrophages.     

Interstitial deletion of bands 4q12-->q13.1: case report and review of proximal 4q deletions.

We report a 6 year old child with a small de novo interstitial deletion of proximal 4q, karyotype 46,XX,del(4)(pter-->q12::q13.1-->qter). She has made good developmental progress and attends normal school with minimal assistance. We review published reports and clinical findings in patients with proximal 4q deletions.     

Survey of adolescents with severe intellectual handicap.

A diagnostic survey was undertaken of children aged 11 to 19 years in Tameside with severe learning difficulties (intelligence quotient less than or equal to 50). Eighty-two children were identified and their medical records reviewed. A specific diagnosis for the retardation was documented in 25 (30%) of the children, 18 of whom had Down''s syndrome. A probable aetiology or a disorder of unknown aetiology had been identified in a further 21 (26%) children. To confirm the existing diagnosis, identify new diagnoses, and offer genetic counselling, the parents of 63 children were offered detailed reassessment of their child. Fifty three children were reviewed, and a specific disorder identified in 25 out of 31 previously undiagnosed children. The most frequent diagnoses made were fragile X syndrome and Rett''s syndrome. On completion of the survey, 61 of the 82 children (74%) had a specific diagnosis or probable aetiology identified, 12 (15%) had associated disorders such as cerebral palsy, and in only nine of the 82 children (11%) were there no clues at all to the cause of their retardation.     

Use of PCR in the diagnosis of early syphilis in the United Kingdom

OBJECTIVES: To evaluate a Treponema pallidum polymerase chain reaction (PCR) test in the laboratory diagnosis of early syphilis in the United Kingdom. Subjects and setting: Men and women attending genitourinary medicine clinics in England. METHODS: A trial PCR service was offered for the analysis of swabs of ano-genital or oral ulcers suspected to be syphilitic in origin. Clinical details, results of treponemal serology, and other relevant laboratory tests carried out by the sending laboratories were obtained retrospectively by questionnaire. RESULTS: Data from 98 patients, representing 100 episodes of ulceration, were analysed. The majority of patients (70) attended clinics in the Greater Manchester area. Eighty six patients were male and 58 were men who have sex with men (MSM), of whom 24 were HIV positive. PCR results agreed with the clinical diagnosis for 95 patients; samples from 26 patients were PCR positive and serologically diagnosed as primary (18) or secondary (8) syphilis, whereas 70 patients had PCR negative samples and were not diagnosed as having active syphilis. These data include two HIV positive patients who were PCR positive 12 and 21 days before their treponemal seroconversion. One positive PCR result was not supported by positive treponemal serology (this patient coincidentally received a 10 day course of co-amoxiclav 1 week after sampling). Three patients had negative PCR results but positive syphilis serology. The sensitivity, specificity, positive and negative predictive value for primary syphilis were 94.7%, 98.6%, 94.7%, and 98.6%, respectively, and for secondary syphilis these were 80.0%, 98.6%, 88.9%, and 97.2%, respectively. CONCLUSION: PCR is a sensitive and specific test for T pallidum, and an important adjunct to dark ground microscopy and treponemal serology in diagnosing infectious syphilis in the United Kingdom.     

Comorbid personality impairment in body dysmorphic disorder

Personality impairment was evaluated in 17 body dysmorphic disorder (BDD) patients undergoing a treatment study of clomipramine versus desipramine. Semistructured interviews were administered using both categorical (Structured Clinical Interview for DSM [SCID II]) and dimensional (Dimensional Assessment of Personality Impairment [DAPI]) methods. Personality measures were also correlated with a range of clinical variables (severity of BDD and depressive symptoms, age, duration of illness, and response to treatment). A secondary aim of the study was to provide preliminary validation for the DAPI. Consistent with previous studies, BDD patients showed considerable personality pathology. By SCID II, patients met criteria for a mean of 2.53 personality disorder diagnoses; 87% of patients met criteria for at least 1 diagnosis and 53% for more than 1. Cluster C diagnoses were the most common. Mean scores for the DAPI were 2.63 (3 = mild impairment) to 6.41 (7 = severe impairment), averaging 5.26 (5 = moderate). With regard to the DAPI, the results provided preliminary evidence of good reliability and validity. Moreover, both personality measures were highly intercorrelated. Although SCID II diagnoses correlated with baseline depression (Hamilton Rating Scale for Depression [HRSD]) scores, there were few other significant correlations between personality and other clinical variables. Of note, however, treatment responders demonstrated less personality impairment than nonresponders. The finding that personality measures were highly intercorrelated but, on the whole, not well correlated with other clinical measures supports the distinct and dissociable nature of personality phenomena in BDD. Despite the small sample size, these results suggest that personality impairment appears to be significant factor in BDD and may even play a role in treatment response.     

Primary osteosarcoma of the skull

Primary osteogenic sarcoma of the skull is an exceedingly rare condition. An adult male patient is described, who had a painless swelling in the right forehead that had rapidly enlarged in the previous 6 months. Radiological investigations showed a large destructive mass lesion involving the right side of the frontal bone with extension into the frontal sinus, causing marked extradural compression of brain parenchyma. Histopathological examination confirmed the lesion to be primary osteogenic sarcoma.     

Expression of differential nitric oxide synthase isoforms in human normal gastric mucosa and gastric cancer tissue

The present study investigated the expression and distribution of three isoforms of nitric oxide synthase (NOS) in different anatomical regions of the human stomach and in gastric neoplastic tissues by immunohistochemistry using specific antibodies. Intracellular localization of individual isoenzymes of NOS was detected in normal gastric mucosa. Gastric cancer tissues had a marked reduction of all three NOS isoforms expression. The expression of the endothelial NOS, neuronal NOS and inducible NOS in the tumor tissue was significantly lower than in normal gastric mucosa (P = 0.01, P = 0.02, P < 0.01, respectively). In the tumor tissue the expression of inducible NOS was significantly lower than the expression of both constitutive forms of NOS (P < 0.01). There was a tendency to higher expression of both constitutive forms of NOS in earlier stages T2 of the tumor compared to advanced T4 tumor. In contrast, the expression of inducible NOS was higher than in the advanced T4 tumor than in the earlier stages T2 of the tumor. The mapping of the expression of endothelial NOS, neuronal NOS and inducible NOS in human stomach showed higher expression of NOS isoforms in the distal third than in the proximal third of the stomach (P = 0.03, P = 0.04, P = 0.01, respectively). We conclude that there is greater expression of NOS in the stomach corpus and in antrum than in the proximal third of the normal human stomach mirroring the anatomical predilection of common pathological changes in this part of the human stomach. Furthermore, there was loss of the expression of individual isoenzymes in gastric neoplasms.      

Central venous catheter tip position and malfunction in a paediatric oncology unit

An audit of 151 central venous catheters (CVCs) in 118 children with malignant disease was carried out over 20 months. The types included 31 valved silastic (Groshong), 58 non-valved silastic (Hickman), and 62 non-valved polyurethane (Cuff Cath) CVCs. There was no difference between the three groups with regard to the clinical diagnosis. The mean patient age at catheter insertion was 5.5 years and the mean weight 21.6 kg. None of the catheter types were associated with an increased risk of problems at insertion, migration, mechanical damage, blockage, sampling, or catheter infection. The incidence of catheter infection was 1.4/1,000 catheter days. Exit-site infection was less frequent with Groshong CVCs (P <0.05), which were in situ for the shortest period. The risk of problems with blood sampling was significantly increased in those catheters whose tip was sited outside the right atrium (P <0.005). For the 60 CVCs removed electively, the mean duration in situ was similar for all catheter types; 43 were removed following a problem. Of these, Groshong catheters were in situ for the shortest period (P = 0.05), probably as a result of delayed anchoring of the cuff. The tip position was the single most important determinant in the correct functioning of CVCs, irrespective of the type of catheter. Intraoperative screening of the tip position at catheter insertion is therefore mandatory for optimal catheter functioning.