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.     

Metabolic effects of i.v. propacetamol, metamizol or external cooling in critically ill febrile sedated patients

We have measured the metabolic response to sequential administration of propacetamol, metamizol and/or external cooling in 20 febrile patients under sedation and analgesia and during mechanical ventilation. There was no change in temperature (T degree) after propacetamol therapy, whereas after metamizol only a small decrease was noted (from 38.9 (SEM 0.2) to 38.5 (0.3) degrees C; P = 0.02). External cooling produced a significant decrease in T degree (39.1 (0.2) to 37.1 (0.2) degrees C; P < 0.0001) accompanied by a decrease in energy expenditure (EE) (2034 (73) to 1791 (88) kcal day-1; P < 0.004). Heart rate and minute ventilation decreased significantly in parallel. There were no other changes in haemodynamics or pulmonary gas exchanges. We conclude that propacetamol and metamizol did not produce a clinically significant decrease in T degree in febrile ICU patients whereas external cooling decreased both T degree and EE. The parallel decrease in body temperature and EE seemed to be related to opioid administration or sedation, or both.      

Probe "balloon on a wire" ultra-low-profile coronary catheter: results of PTCA in 107 patients

A new low-profile "balloon-on-a-wire" angioplasty catheter, the Probe (USCI), was used in 107 patients over a 4-month period. Twenty-nine patients had stable angina, 59 had unstable angina, and 19 had had myocardial infarction (MI) 3 to 15 days prior to the procedure; 71 patients had single-vessel and 36 had multi-vessel disease. In this series, 57 lesions were defined as complex. Successful dilatation was defined as a residual stenosis of less than 30%. Of 132 non-total obstructions, 127 (97%) were successfully dilated. Two distal lesions could not be reached, two lesions could not be crossed by the balloon, and a distal lesion dilatation resulted in acute closure in one case. Of 19 total obstructions, 16 (84%) were successfully dilated (mean residual stenosis 23%). The wire tip was unable to cross the lesion in the three unsuccessful procedures. Seven complications occurred in the series, all involving non-total obstructions: closure of a distal vessel and a side branch caused no clinical symptoms or EKG changes; three local dissections were tacked back with repeat dilatation; and two longitudinal dissections caused no apparent reduction in luminal diameter. The Probe's low-profile and exceptional trackability enabled it to cross very tight lesions with minimal trauma to the vessel wall. The high degree of conformability of the PET balloon minimizes vessel straightening or sheer forces and appears to reduce the potential for dissection. The device may therefore extend the indications and ease of PTCA while reducing complications of the procedure.     

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.