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.     

Primary repair of tetralogy of Fallot in infancy

From June 1983 to April 1988, 100 consecutive infants with symptomatic tetralogy of Fallot (without pulmonary atresia) were operated on. Ages ranged from 0.5 to 12 months (mean 7.3 +/- 3.7). Twenty patients were 0.5 to 3 months, 21 were 3 to 6 months, and 59 were 6 to 12 months of age. Mean weight was 6.5 kg +/- 1.7. Seventy patients received a transannular patch. The hospital mortality rate was 3% and there were no late deaths. Cumulative follow-up was 180 patient-years. Causes of death included hypoplastic pulmonary arteries (4 and 5 months old) and right ventricular failure (4 months old). The most important factors influencing right ventricular outflow tract reconstruction were neither weight (p = 0.90) nor age (p = 0.05) but rather were the ratio between weight and pulmonary arterial outflow tract diameter (p = 0.0005) and the ratio between body surface area and pulmonary arterial outflow tract diameter (p less than 0.0001). The last 48 patients were operated on with no deaths. During this period, operative management differed essentially in myocardial protection with blood cardioplegia. The predicted 30-day survivorship after repair was 90% to 99% (95% confidence limits). No ventricular arrhythmias have been detected after repair (mean follow-up 22.2 months). Mean right ventricular/left ventricular end-diastolic dimension ratio was (0.53 +/- 0.10 with M-mode echocardiography. These early results encourage us to proceed with primary repair of infants with symptomatic tetralogy of Fallot thanks to improved surgical management and enhanced myocardial protection.     

Pseudo-angiomatous hyperplasia of mammary stroma: a case with gigantomastia

Pseudo-angiomatous hyperplasia of mammary stroma (PASH) is a histopathological entity which is a microscopic fortuitous finding in mammary biopsies performed for different reasons. It may be symptomatic and appears then as a palpable lump. The term pseudo-angiomatous emphasizes the characteristic aspect of the stroma simulating a vascular tumor. We report a case of PASH in a 71 year-old woman who presented a recurring breast mass with rapid swelling of the mammary gland (70 x 60 x 20 cm) treated by mastectomy. PASH must be distinguished from a well-differentiated angiosarcoma. It is ruled out by immunohistochemistry.     

Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction

Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally identified on the tumor cell surface as an inducer of matrix metalloproteinase (MMP) production in neighboring fibroblasts. Here we demonstrate a role for EMMPRIN in MMP induction during corneal wound healing. MMP and EMMPRIN expression was analyzed in normal and ulcerated human corneas, as well as in corneal epithelial and stromal cells in culture using confocal microscopy, zymography, immunoblots, and real-time polymerase chain reaction. In normal cornea EMMPRIN was predominantly expressed in the epithelium but was markedly induced in the anterior stroma of ulcerated corneas. This coincided with MMP-2 induction that co-localized with EMMPRIN at the epithelio-stromal boundary. The role of epithelial-stromal interaction in MMP induction was investigated in an in vitro co-culture system and demonstrated an induction and co-localization of EMMPRIN and MMP-2 in the fibroblasts at the interface with epithelial cells. Direct contact of fibroblasts with EMMPRIN-containing purified epithelial cell membranes also induced MMP-1, MMP-2, and EMMPRIN and this was inhibited by a blocking anti-EMMPRIN antibody, suggesting that EMMPRIN was primarily responsible for this induction. These findings, and the up-regulation of EMMPRIN by epidermal growth factor and transforming growth factor-beta, demonstrate a role for EMMPRIN in wound healing and suggest that sustained local up-regulation of EMMPRIN and MMPs in chronic situations in which healing is delayed may lead to excessive matrix degradation and corneal melts.     

Duplication 3q(q21 → qter) without limb anomalies

We report on a 2.5-month-old boy with hypertelorism, hypertrichosis, anteverted nostrils, malformed ears, thin lips, downturned corners of the mouth, micrognathia, short neck, cryptorchidism, and bilateral simian creases without limb anomalies. Cytogenetic studies showed a duplication 3q → qter 46,XY,der(6),t(3;6)(q21;p25)pat. The absence of limb anomalies is noteworthy; all 12 previously reported patients with the same duplication had limb anomalies. The uniqueness of this report provokes speculations regarding limb morphogenesis in embryos with chromosome anomalies. The concepts of chronogenetics, heterochrony, and developmental field defects appear relevant to yet another set of patients with chromosome anomalies.     

Increased expression of periplasmic Cu,Zn superoxide dismutase enhances survival of Escherichia coli invasive strains within nonphagocytic cells

We have studied the influence of periplasmic Cu,Zn superoxide dismutase on the intracellular survival of Escherichia coli strains able to invade epithelial cells by the expression of the inv gene from Yersinia pseudotuberculosis but unable to multiply intracellularly. Intracellular viability assays, confirmed by electron microscopy observations, showed that invasive strains of E. coli engineered to increase Cu,Zn superoxide dismutase production are much more resistant to intracellular killing than strains containing only the chromosomal sodC copy. However, we have found only a slight difference in survival within HeLa cells between a sodC-null mutant and its isogenic wild-type strain. Such a small difference in survival correlates with the very low expression of this enzyme in the wild-type strain. We have also observed that acid- and oxidative stress-sensitive E. coli HB101(pRI203) is more rapidly killed in epithelial cells than E. coli GC4468(pRI203). The high mortality of E. coli HB101(pRI203), independent of the acidification of the endosome, is abolished by the overexpression of sodC. Our data suggest that oxyradicals are involved in the mechanisms of bacterial killing within epithelial cells and that high-level production of periplasmic Cu,Zn superoxide dismutase provides bacteria with an effective protection against oxidative damage. We propose that Cu,Zn superoxide dismutase could offer an important selective advantage in survival within host cells to bacteria expressing high levels of this enzyme.