Thrombolysis and Angioplasty in Myocardial Infarction (TAMI-1) trial: influence of infarct location on arterial patency, left ventricular function and mortality

The influence of infarct location on arterial patency, left ventricular function and mortality after 150 mg of intravenous recombinant tissue-type plasminogen activator (rt-PA) and selective coronary angioplasty was studied in 386 patients with acute myocardial infarction. In 329 patients with acute and 1 week angiograms, the 90 min infarct-related artery patency rate after rt-PA in the left anterior descending, the left circumflex and the right coronary artery was 77, 68 and 68%, respectively. Angioplasty, performed in half the patients, resulted in a final acute patency rate of 93%, which was not related to arterial distribution. Repeat catheterization and revascularization were required in 12% of patients before day 7 and were independent of arterial distribution. The reocclusion rate for the right coronary artery (21%) was higher than that for the left anterior descending (12%) or left circumflex (5%) artery (p = 0.01). Acute and 1 week contrast ventriculograms suitable for analysis were available in 266 patients. Whereas serial left ventricular ejection fraction did not improve during the course of this study, serial regional wall motion (centerline chord method) improved in each arterial distribution. The in-hospital mortality rate of 6% was not related to arterial distribution, although death was twice as likely with proximal compared with distal lesions. Ten of 11 patients who died in the group with the left anterior descending artery as the infarct-related artery had a lesion proximal to the first septal perforator branch.(ABSTRACT TRUNCATED AT 250 WORDS)     

HPV frequency in penile carcinoma of Mexican patients: important contribution of HPV16 European variant

The role of human papillomavirus (HPV) infection in penile carcinoma (PeC) is currently reported and about half of the PeC is associated with HPV16 and 18. We used a PCR-based strategy by using HPV general primers to analyze 86 penile carcinomas paraffin-embedded tissues. Some clinical data, the histological subtype, growth pattern, and differentiation degree were also collected. The amplified fragments were then sequenced to confirm the HPV type and for HPV16/18 variants. DNA samples were also subjected to relative real time PCR for hTERC gene copy number. Some clinical data were also collected. Global HPV frequency was 77.9%. Relative contributions was for HPV16 (85%), 31 (4.4%), 11 (4.4%), 58, 33, 18, and 59 (1.4% each one). Sequence analysis of HPV16 identified European variants and Asian-American (AAb-c) variants in 92% and in 8% of the samples, respectively. Furthermore hTERC gene amplification was observed in only 17% of the cases. Our results suggest that some members of HPV A9 group (represented by HPV16, 58, and 31) are the most frequent among PeC patients studied with an important contribution from HPV16 European variant. The hTERC gene amplification could be poorly related to penile epithelial tissue.     

CMV driven CD8 T-cell activation is associated with acute rejection in lung transplantation

Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8⁺ T-cell activity post-transplant. Peripheral and lung CMV-specific CD8⁺ T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8⁺ T-cells in the lung may play a role in promoting acute rejection.     

Immunodominance of HLA-B27-restricted HIV KK10-specific CD8+ T-cells is not related to naïve precursor frequency

The factors that determine the immunodominance, efficacy and almost ubiquitous presence of CD8⁺ T-cell responses to the HLA-B27-restricted HIV-1 p24 Gag-derived KK10 epitope remain to be fully elucidated. Here, we show that neither the precursor frequency nor the priming capacity of KK10-reactive CD8⁺ T-cells within the naïve pool differ substantially in comparison to other specificities. These data implicate alternative mechanisms in the relative protection conferred by CD8⁺ T-cell responses to this epitope.     

Loss of β-Catenin Induces Multifocal Periosteal Chondroma-Like Masses in Mice

Osteochondromas and enchondromas are the most common tumors affecting the skeleton. Osteochondromas can occur as multiple lesions, such as those in patients with hereditary multiple exostoses. Unexpectedly, while studying the role of β-catenin in cartilage development, we found that its conditional deletion induces ectopic chondroma-like cartilage formation in mice. Postnatal ablation of β-catenin in cartilage induced lateral outgrowth of the growth plate within 2 weeks after ablation. The chondroma-like masses were present in the flanking periosteum by 5 weeks and persisted for more than 6 months after β-catenin ablation. These long-lasting ectopic masses rarely contained apoptotic cells. In good correlation, transplants of β-catenin-deficient chondrocytes into athymic mice persisted for a longer period of time and resisted replacement by bone compared to control wild-type chondrocytes. In contrast, a β-catenin signaling stimulator increased cell death in control chondrocytes. Immunohistochemical analysis revealed that the amount of detectable β-catenin in cartilage cells of osteochondromas obtained from hereditary multiple exostoses patients was much lower than that in hypertrophic chondrocytes in normal human growth plates. The findings in our study indicate that loss of β-catenin expression in chondrocytes induces periosteal chondroma-like masses and may be linked to, and cause, the persistence of cartilage caps in osteochondromas.Osteochondromas and enchondromas are the most common tumors affecting the skeleton.^1,2 Osteochondromas are cartilage-covered masses that form near the growth plate and bone surface, whereas enchondromas form within the growth plate and bone marrow. Both types of benign tumors can cause mechanical impairment of movement and also pain due to impingement or compression of nerves and blood vessels, particularly when they are present at multiple sites.^3,4 These benign tumors may become malignant.^5–7 The potential for malignant progression is greater in patients with syndromes, such as Ollier disease, Maffucci syndrome, or hereditary multiple exostoses (HME), the latter also known as multiple osteochondroma.^5–7 Current treatments largely rely on surgical excision.^3,8 Both benign and malignant cartilage tumors are generally resistant to chemotherapy and radiotherapy.^5,9 Thus, a better understanding of the cellular and molecular mechanisms underlying cartilage tumor formation and growth is critical for the development of new therapeutic strategies and treatments.Recent studies have indicated that several genes play important roles in cartilage tumor formation.^4,5 Hopyan et al¹⁰ found mutations in parathyroid hormone receptor 1 (PTHR1) in patients with multiple enchondromas. These authors generated mice harboring the same PTHR1 mutations that displayed a similar enchondroma formation. In addition, they found that the PTHR1 mutations caused constitutive activation of hedgehog signaling in cultured chondrocytes and that overexpression of Gli2, a downstream molecule of hedgehog signaling, induced enchondromas in mice.¹⁰ In the follow-up studies, however, it was found that certain cohorts of enchondromatosis patients do not have PTHR1 mutations¹¹ and that enchondroma formation may actually be independent of hedgehog signaling.¹² Thus, the pathogenesis of enchondroma formation remains to be clarified.Mutations in EXT1 and EXT2 genes have been associated with hereditary multiple exostoses (HME) (multiple osteochondroma).^5–7 Mutations in these genes are often missense or frame shift and cause synthesis of lower levels of (and shorter) heparan sulfate chains.^4,5 This is because EXT1 and EXT2 encode Golgi-associated enzymes are responsible for the polymerization of the chains.¹³ Insufficiency of heparan sulfate-rich proteoglycans is thought to be a cause of osteochondroma formation.^4,5,13 Heparan sulfate proteoglycans are important for the regulation of many signaling pathways that include hedgehog, bone morphogenetic protein, fibroblast growth factor, and Wnt pathways.^13,14 All of these pathways are critical regulators for chondrogenic differentiation and chondrocyte differentiation.^15,16 It is likely that dysregulation of these signaling pathways resulting from heparan sulfate deficiency may trigger abnormal behavior of growth plate chondrocytes or induce ectopic chondrogenic differentiation, leading to ectopic cartilage formation. Recently, several Ext mutant mouse lines have been established.^17–19 All of these transgenic mouse lines show multifocal ectopic cartilaginous masses with microscopical and structural similarities to osteochondromas found in HME patients.^17–19 The cellular and molecular mechanisms underlying EXT mutation-associated chondroma formation, however, remains largely unclear.The Wnt/β-catenin signaling pathway is essential for regulation of normal cartilage development, maintenance of permanent cartilage, and growth plate function.^20–24 Previous reports have shown that inactivation of this signaling pathway impairs cartilage and skeletal development. Conditional ablation of the β-catenin gene in limb skeletogenic cells induces a delay in endochondral bone formation and the formation of abnormal cartilaginous masses during embryonic development.^25–27 In addition, overexpression of a Wnt antagonist strongly inhibits both hypertrophy of chondrocytes and progression of endochondral ossification.²⁸ Recently, we generated compound transgenic mice in which we induced postnatal conditional ablation of β-catenin in cartilage.²⁴ We found that the resulting β-catenin deficiency impaired growth plate function and skeletal growth. In addition, the mice developed ectopic cartilaginous masses located near the bone surface but not within the bone marrow. In the present study, we characterized the pathohistology of these ectopic cartilaginous masses and investigated their possible cell origin and fate, and also related the findings to human osteochondromas.