Mechanism of myocardial "stunning"

Among the numerous mechanisms proposed for myocardial stunning, three appear to be more plausible: 1) generation of oxygen radicals, 2) calcium overload, and 3) excitation-contraction uncoupling. First, the evidence for a pathogenetic role of oxygen-derived free radicals in myocardial stunning is overwhelming. In the setting of a single 15-minute coronary occlusion, mitigation of stunning by antioxidants has been reproducibly observed by several independent laboratories. Similar protection has been recently demonstrated in the conscious animal, that is, in the most physiological experimental preparation available. Furthermore, generation of free radicals in the stunned myocardium has been directly demonstrated by spin trapping techniques, and attenuation of free radical generation has been repeatedly shown to result in attenuation of contractile dysfunction. Numerous observations suggest that oxyradicals also contribute to stunning in other settings: after global ischemia in vitro, after global ischemia during cardioplegic arrest in vivo, and after multiple brief episodes of regional ischemia in vivo. Compelling evidence indicates that the critical free radical damage occurs in the initial moments of reflow, so that myocardial stunning can be viewed as a sublethal form of oxyradical-mediated "reperfusion injury." Second, there is also considerable evidence that a transient calcium overload during early reperfusion contributes to postischemic dysfunction in vitro; however, the importance of this mechanism in vivo remains to be defined. Third, inadequate release of calcium by the sarcoplasmic reticulum, with consequent excitation-contraction uncoupling, may occur after multiple brief episodes of regional ischemia, but its role in other forms of postischemic dysfunction has not been explored. It is probable that multiple mechanisms contribute to the pathogenesis of myocardial stunning. The three hypotheses outlined above are not mutually exclusive and in fact may represent different steps of the same pathophysiological cascade. Thus, generation of oxyradicals may cause sarcoplasmic reticulum dysfunction, and both of these processes may lead to calcium overload, which in turn could exacerbate the damage initiated by oxygen species. The concepts discussed in this review should provide not only a conceptual framework for further investigation of the pathophysiology of reversible ischemia-reperfusion injury but also a rationale for developing clinically applicable interventions designed to prevent postischemic ventricular dysfunction.     

Neurological symptoms in children with intussusception

Aim:  The classical combination of abdominal pain, vomiting, rectal blood loss and a palpable abdominal mass is only present in a minority of children with intussusception. Neurological signs and symptoms have been described, but are not a well understood phenomenon. We performed a retrospective study to ascertain the frequency and nature of these symptoms and to describe the characteristics of the patients presenting in this atypical way.
Methods:  The records of 58 children presenting with intussusception from 2003 to 2008 were reviewed for abdominal and neurological signs and symptoms, duration of symptoms and effectiveness of treatment.
Results:  In 10 out of 58 patients (17%), one or more neurological symptoms were recorded at presentation, with lethargy being the most frequent, followed by hypotonia and fluctuating consciousness. The patients with neurological abnormalities were significantly younger and presented with a shorter duration of symptoms. Therapy was more invasive, although not statistically significant, in this patient category.
Conclusion:  Intussusception should be considered in the differential diagnosis in young children presenting with lethargy, hypotonia and/or sudden alterations of consciousness even in the absence of the classical symptoms of intussusception.     

Autopsies of sudden infant death syndrome—classification and epidemiology

An enquiry into sudden infant death syndrome (SIDS) in 1987 furnished us with detailed epidemiological data for 281 cases that underwent a thorough post-mortem examination. This analysis uses these data to evaluate the role the autopsy plays in explaining sudden death. The cases were classified into three diagnostic groups: explained causes of death (group 1), unexplained deaths with anomalies (group 2), and no anomaly (group 3). These 281 cases show the three essential features that characterize SIDS: over-representation of males, increased deaths during the second and third months of life, and increased deaths during winter. The autopsy examination revealed that many of these deaths had a medical explanation. Almost half were assigned to group 1. At the time of autopsy, no precise pathology could be diagnosed for 147 deaths; of these, 140 showed histological anomalies. There were only seven sudden deaths for which no abnormal sign was evident at the autopsy. These results are compared with those of similar studies and discussed in connection with three factors: the initial selection of cases, the nature and degree of the investigations, and the possible interpretations of the symptoms uncovered.     

Endothelin receptor antagonists: structures, synthesis, selectivity and therapeutic applications

Endothelin (ET) was discovered in 1988 and is the most potent vasoconstrictive peptide known to date. It exists in three isoforms (ET-1 to ET-3) and acts on two endothelin receptor subtypes, the endothelin-A (ET(A))-receptor and the endothelin-B (ET(B))-receptor. Endothelin receptor antagonists are novel therapeutics in clinical development for different cardiovascular, cerebrovascular, and renal diseases. Several different structural classes of endothelin receptor antagonists have been discovered within the last decade, starting from peptidic- and peptidomimetic structures to small organic molecules suitable as therapeutics for oral administration. Focussing on the small organic molecules, the different structural classes of ET-receptor antagonists are described with respect to synthesis, structure-activity-relationships, receptor-subtype-selectivity profile, and where possible, intended therapeutic indications.     

Prognostic relevance of MAGE-A4 tumor antigen expression in transitional cell carcinoma of the urinary bladder: a tissue microarray study

TAAs of the MAGE family are mostly studied as targets of specific immune responses. Their potential relevance as tumor markers has also been underlined. We used a MAb, 57B, recognizing MAGE-A4 protein in paraffin-embedded sections, to evaluate its expression in bladder cancers by employing TMA including 2,317 samples from 1,849 patients. In 2,090/2,317 cases (90.2%), immunostaining yielded interpretable results. Since for some patients more than 1 sample was available, only interpretable first biopsies (n = 1,628) were considered. MAGE-A4 protein was expressed at significantly (p < 0.001) higher frequency in squamous (25/55, 45.5%) than in adeno (4/15, 26.7%), sarcomatoid (4/14, 28.6%), small cell (5/20, 25%) or transitional cell (281/1,522, 18.5%) carcinomas. In TCCs, overall MAGE-A4 positivity was significantly correlated with invasive phenotype (p < 0.001) and high tumor grade (p < 0.0001). Clinical data from 908 TCC patients were retrospectively evaluated, revealing that strong 57B staining was highly significantly associated with decreased tumor-specific survival (p < 0.0001). These data suggest that evaluation of MAGE-A4 protein expression is useful in the identification of groups of TCCs characterized by severe prognosis, thus possibly providing indications for early MAGE TAA-targeted immunotherapy.     

Cerebral trypanosomiasis and AIDS

A 36 year-old black female, complaining of headache of one month's duration presented with nausea, vomiting, somnolence, short memory problems, loss of weight, and no fever history. Smoker, intravenous drugs abuser, promiscuous lifestyle. Physical examination: left homonimous hemianopsia, left hemiparesis, no papilledema, diffuse hyperreflexia, slowness of movements. Brain CT scan: tumor-like lesion in the splenium of the corpus calosum, measuring 3.5 x 1.4 cm, with heterogeneous enhancing pattern, suggesting a primary CNS tumor. Due to the possibility of CNS infection, a lumbar puncture disclosed an opening pressure of 380 mmH(2)0; 11 white cells (lymphocytes); glucose 18 mg/dl (serum glucose 73 mg/dl); proteins 139 mg/dl; presence of Trypanosoma parasites. Serum Elisa-HIV tests turned out to be positive. Treatment with benznidazole dramatically improved clinical and radiographic picture, but the patient died 6 weeks later because of respiratory failure. T. cruzi infection of the CNS is a rare disease, but we have an increasing number of cases in HIV immunocompromised patients. Diagnosis by direct observation of CSF is uncommon, and most of the cases are diagnosed by pathological examination. It is a highly lethal disease, even when properly diagnosed and treated. This article intends to include cerebral trypanosomiasis in the differential diagnosis of intracranial space-occupying lesions, especially in immunocompromised patients from endemic regions.     

Insulins today and beyond

The advent of insulin almost 80 years ago revolutionised treatment of diabetes and must be one of the most outstanding achievements of twentieth century medicine. Since then, there has been an ever-increasing awareness and acceptance of the need to achieve and sustain near-normoglycaemia to delay onset and retard progression of diabetic angiopathy. Physiological insulin replacement is therefore central to management of patients with diabetes who are unable to make [corrected] insulin. Insulin formulations, treatment strategies, and methods and routes of delivery have changed much, with more and more options for monitoring the effect on blood glucose concentrations. Patients with type 1 and type 2 diabetes need insulin much more aggressively than previously. Parallel developments in glucose-sensing technologies are welcomed as an integral part of safe and optimum implementation of insulin replacement therapy.