Enzymatic escharolysis with nexobrid® on partial thickness burn wounds: pre- and post-debridement histological assessment.

Enzymatic escharolysis is an innovative, non-surgical treatment method for severe burn patients as it allows very early, nontraumatic removal of necrotic tissue even on patients whose overall clinical conditions would mandate delaying traditional surgical escharectomy. The aim of this work was to examine aspects related to the "quality" of enzymatic debridement, which is inherently different from surgical debridement. To this end, biopsies harvested from partial thickness burn wounds, before and after enzymatic treatment, were histologically assessed. As is well known, surgical escharectomy removes the necrosis as well as some of its neighbouring healthy tissue, sharply and radically, leaving a perfectly clean and viable wound bed. On the other hand, enzymatic escharolysis is more selective, as it completely wipes out the necrotic portion while sparing unharmed and partially damaged tissue. In this study, only mid-deep partial thickness wounds were examined, and it was observed that partially damaged dermis was always spared by the lytic action. This dermis, however, showed some "homogenization" characteristics, had few vital skin annexes in it, and therefore looked very similar to the scaffold of dermal matrices currently available on the market. This scaffold should be safeguarded with a view to possibly achieving a more complete and functional spontaneous tissue regeneration. Conversely, if this dermal portion is mismanaged, it could desiccate, thus leading to the formation of a neo-eschar with unpredictable clinical evolution. Understanding how escharolysis actually works allowed us to extrapolate fruitful usage suggestions to optimize the procedure and fully exploit its potential.

La détersion enzymatique est une technique innovante non chirurgicale permettant l'ablation très précoce et non traumatique des tissus nécrosés même chez des patients dont l'état général nécessiterait de repousser une excision chirurgicale. Le but de ce travail était d'évaluer la « qualité ¼ du débridement enzymatique, par essence différent du traitement chirurgical. À cette fin, nous avons examiné histologiquement des biopsies réalisées avant et après détersion. Il est bien connu que la chirurgie emporte totalement et radicalement la nécrose et une partie du tissu environnant, laissant en place un tissu parfaitement propre et viable. Le débridement enzymatique est plus sélectif, emportant tout le tissu nécrosé sans affecter les tissus sains ou viables. Cette étude ne s'est intéressée qu'aux brûlures intermédiaires et nous avons observé que les régions saines étaient toujours préservées. Ce derme restant apparaît toutefois homogénéisé, avec peu d'annexes viables ce qui fait penser aux matrices des dermes artificiels actuellement commercialisés. Il doit être préservé afin de promouvoir une régénération tissulaire complète et fonctionnelle. Ainsi, si ce derme restant n'est pas correctement pris en charge, il peut se dessécher et aboutir à la formation d'un nouvel escarre, d'évolution imprévisible. Le compréhension du mécanisme exact de la lyse de la brûlure permet de développer des protocoles d'optimisation de la technique de lyse enzymatique.

Classical and recent advances in the treatment of inflammatory bowel diseases

Crohn's disease (CD) and ulcerative colitis (UC) are intestinal disorders that comprise the inflammatory bowel diseases (IBD). These disorders have a significant effect on the quality of life of affected patients and the increasing number of IBD cases worldwide is a growing concern. Because of the overall burden of IBD and its multifactorial etiology, efforts have been made to improve the medical management of these inflammatory conditions. The classical therapeutic strategies aim to control the exacerbated host immune response with aminosalicylates, antibiotics, corticosteroids, thiopurines, methotrexate and anti-tumor necrosis factor (TNF) biological agents. Although successful in the treatment of several CD or UC conditions, these drugs have limited effectiveness, and variable responses may culminate in unpredictable outcomes. The ideal therapy should reduce inflammation without inducing immunosuppression, and remains a challenge to health care personnel. Recently, a number of additional approaches to IBD therapy, such as new target molecules for biological agents and cellular therapy, have shown promising results. A deeper understanding of IBD pathogenesis and the availability of novel therapies are needed to improve therapeutic success. This review describes the overall key features of therapies currently employed in clinical practice as well as novel and future alternative IBD treatment methods.

Classical and recent advances in the treatment of inflammatory bowel diseases.

Crohn's disease (CD) and ulcerative colitis (UC) are intestinal disorders that comprise the inflammatory bowel diseases (IBD). These disorders have a significant effect on the quality of life of affected patients and the increasing number of IBD cases worldwide is a growing concern. Because of the overall burden of IBD and its multifactorial etiology, efforts have been made to improve the medical management of these inflammatory conditions. The classical therapeutic strategies aim to control the exacerbated host immune response with aminosalicylates, antibiotics, corticosteroids, thiopurines, methotrexate and anti-tumor necrosis factor (TNF) biological agents. Although successful in the treatment of several CD or UC conditions, these drugs have limited effectiveness, and variable responses may culminate in unpredictable outcomes. The ideal therapy should reduce inflammation without inducing immunosuppression, and remains a challenge to health care personnel. Recently, a number of additional approaches to IBD therapy, such as new target molecules for biological agents and cellular therapy, have shown promising results. A deeper understanding of IBD pathogenesis and the availability of novel therapies are needed to improve therapeutic success. This review describes the overall key features of therapies currently employed in clinical practice as well as novel and future alternative IBD treatment methods.

Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.

Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease.

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.

Constitutive expression of cyclooxygenase-2 in the neuromuscular compartment of normal human colon.

Prostaglandins regulate various functions throughout the gastrointestinal system. Their biosynthesis depends on cyclooxygenase isoforms, named COX-1 and COX-2. The initial hypothesis that COX-2 is an inducible enzyme has been challenged and its constitutive expression in the stomach has been established. In this study, an immunohistochemical analysis was performed to evaluate the distribution and cellular localization of COX-2 in normal human colon. Colonic surgical specimens were processed for COX-2, protein HuC/HuD, neurofilament, S-100 protein and CD117/c-kit immunodetection. COX-2 protein was found to be constitutively expressed in the colonic wall: detectable amounts were localized in mucosal, submucosal and muscular layers, mainly in the neuromuscular compartment. In particular, COX-2 was expressed in muscularis mucosae, submucosal ganglia, longitudinal muscle layer and myenteric ganglia, the neurons of which displayed different degrees of immunostaining. Intramuscular interstitial cells of Cajal, regarded as important sites for the regulation of enteric neuromuscular activity, were also partly COX-2 immunoreactive. This study provides a detailed mapping of COX-2 expression in human colon, and allows better understanding of the roles played by this isoenzyme in gut physiology.

Role of electrothrombosis in aneurysm treatment with Guglielmi detachable coils: an in vitro scanning electron microscopic study.

BACKGROUND AND PURPOSE: In the 1990s, the introduction of the Guglielmi detachable coil (GDC) system in clinical practice was followed by extensive clinical use of this endovascular device in the treatment of brain aneurysms. This technology is based on electrothrombosis and electrolytic detachment of platinum coils. Despite the extensive use of this treatment technique, the role of electrothrombosis has not been fully investigated and clarified. An in vitro electron microscopic study of human blood was performed to elucidate the role that electrothrombosis might play in triggering the biologic response of thrombosis of the aneurysmal sac. METHODS: Human blood from five patients was used to fill plastic containers in which GDCs had been deposited. These five patients had subarachnoid hemorrhage and were similar in age and clinical presentation. Electron microscopic studies were performed on GDCs that had been electrically charged and on GDCs that had not. RESULTS: All electron microscopic studies revealed that the electrically charged GDCs were covered by blood elements and fibrin adherent to the surface of the coil. Noncharged GDCs did not have deposits or adhesions of these blood constituents. CONCLUSION: These findings demonstrated that passage of electric current through the GDC induces attraction of blood constituents. This attraction may trigger a thrombotic reaction on the surface of the coil. The greater the time of current application, the more pronounced the cellular reaction and the deposition of fibrin and blood cells on the GDC.

Expression and prognostic significance of urokinase and plasminogen activator inhibitor type-1 in endometrial hyperplasia and cancer.

Proteolytic enzymes, like urokinase (uPA) and plasminogen activator inhibitor type-1 (PAI-1), are involved in remodelling tissues during invasion and metastasis of tumor cells. The purpose of the study is to evaluate the expression and the prognostic significance of these enzymes in endometrial hyperplasia and cancer. We used immunohistochemical staining to localize uPA and PAI-1 antigens and evaluate their expression, and the enzyme-linked immunosorbent assay (ELISA) to measure their levels during the progression of endometrial carcinoma. The results show that the levels of uPA and PAI-1 detection are systematically weak in simplex hyperplasia and are moderate in complex hyperplasia. In the endometrial carcinoma a very strong reaction was observed in the most aggressive variant of epithelial tumors. A positive signal for uPA was found only in the cytoplasm of normal and hyperplastic cells while, in tumors, uPA was present also in the cellular areas surrounding the neoplastic glands and at the apex of the malignant cells. The PAI-1 immunoreactivity was weak to moderate in 95.4% of carcinomas, with a diffuse signal mostly distributed in the cytoplasm of neoplastic cells and tumor stroma. UPA antigen concentrations were significantly higher in endometrial carcinoma than in endometrial hyperplasia (p<0.05) and in normal endometrium (p<0.001). PAI-1 antigen concentrations in carcinoma samples were significantly higher than in normal endometrium (p=0.002), but the difference was not statistically significant with respect to that in endometrial hyperplasia. We did not find any correlation between uPA and PAI-1 concentrations and the standard prognostic parameters for evaluating endometrial carcinoma. In conclusion, this study demonstrates that in hyperplastic endometria and in endometrial carcinoma there is a progressive increase in expression of uPA and PAI-1 than in normal endometrial tissue. In carcinoma tissues, the high expression of uPA is unregulated in the surrounding stroma tissue, particularly in the most aggressive histopathologic variants. UPA and PAI-1 may be factors associated with invasive behavior in endometrial carcinoma independent of other clinicopathological parameters.

Thyroid hormone receptors in neonatal, prepubertal, and adult rat testis.

Thyroid hormone (TH) is involved in the differentiation and development of rat testis, whereas its role in adult testis function is still undefined. The aim of our work has been to further analyze the presence in the testis of rats of various ages of messenger RNA (mRNA) coding the different TH receptor (TR) subtypes using a sensitive assay, such as reverse transcriptase-polymerase chain reaction (RT-PCR). To rule out the possibility of an "illegitimate transcription," we have analyzed both T3-binding capacity of adult rat testis and the presence in the same organ of TR proteins by immunohistochemistry, using specific antibodies directed against the various TR isoforms. Messenger RNA coding for TR alpha1 and alpha2 isoforms was clearly visible in gels prepared from RT-PCR samples obtained from the testis of rats of all ages, including adults, whereas mRNA for the TR beta1-beta2 was absent. The T3 maximal binding capacity (Cmax) by nuclear extracts of testicular homogenates gradually decreased from birth to adulthood, still remaining significantly detectable in adult testis, and represented approximately 1% of the Cmax observed in the liver. The immunostaining technique revealed an intense nuclear staining along the basement membrane of testicular tubules prepared from rats of all ages and incubated with an antipeptide antibody specific for TR alpha1 (alpha1-403). Staining with an antipeptide antibody specific for TR beta1 (beta-62) was never present. Our data show that mRNAs coding for the functional TR alpha1, and also for the still undefined alpha2, are present in the testis of rats of all ages. T3-binding activity and immunohistochemical studies confirmed that the message is translated into proteins. The transcriptional activity clearly decreased from birth to adulthood, but it still remained significantly present. The presence of a TR alpha1 message indicates that the adult rat testis may be directly responsive to T3 and, therefore, suggests an action of TH on rat testis that is not only developmental, but also metabolic.

Fetal intracranial hemorrhage: is minor maternal trauma a possible pathogenetic factor?

OBJECTIVE: The occurrence of fetal intracranial hemorrhage before labor has been repeatedly observed. The aim of this study was to evaluate the sonographic appearance of fetal intracranial hemorrhage in relation to its location. Possible causative factors were also evaluated. DESIGN: Five consecutive cases of fetal intracranial hemorrhage were identified at a single ultrasound unit between 1996 and 1999. In utero magnetic resonance imaging was also performed in four of these cases. Autopsy was performed after pregnancy termination or intrauterine fetal death (one case of each), and neurological follow-up was initiated in the three surviving infants. RESULTS: Hydrocephaly was the predominant sonographic finding associated with intraventricular or subependymal hemorrhage; sonography provided the correct diagnosis in the former (two cases), whereas magnetic resonance imaging was necessary in the latter. Massive intraparenchymal hemorrhage was depicted as an irregular echoic mass, whereas extradural hemorrhage had a cystic appearance. History of minor maternal physical trauma without maternal or placental injury was elicited in all cases. Ultrasound examinations performed before or shortly after the trauma were available in all cases and showed normal fetal anatomy. CONCLUSIONS: The sonographic appearance of fetal intracranial hemorrhage is variable, depending on its location. Even though sonography detected an intracranial anomaly in all cases, magnetic resonance imaging was necessary to establish the hemorrhagic nature of isolated subependymal and extradural hemorrhage. The similarity of histories involving minor maternal physical trauma in all cases, together with the absence of any known factor predisposing to fetal hemorrhage, may suggest that trauma is at least a contributing factor to the pathogenesis of fetal intracranial hemorrhage.

High density of endothelin binding sites in the hearts of infants and children.

Endothelin (ET)-1 peripheral levels are high in children with respect to values of adults, but its pathophysiological significance remains to be established. In these conditions the interaction of ET-1 with its receptors may constitute a clue to the understanding of ET-1 function. Because a direct determination of ET binding sites in the heart of children is lacking, in this study we have attempted an assessment of the ET receptor status in cardiac tissue of infants (<1 year; 0.39 +/- 0.26 (SD) years, n=6) and children (1-14 years; 6.3 +/- 4.9 years, n=7) as well as an evaluation of the receptor modulation as a function of age, associated to the observed decrease of plasma ET levels between infants and children. ET-1 binding sites have also been evaluated in atrium and ventricle membranes of adult subjects recipient of cardiac transplantation (CHF) and of post-mortem cardiac specimens (autopsy) of non cardiac patients. Considering all the pediatric patients (infants +/- children) studied, an affinity constant (Kd) value of 38.2 +/- 6.1 (SEM) pM and a density (Bmax) value of 166.2 +/- 11.6 fmol/mg protein has been obtained for atrium. Similar values have been found in the ventricle. These values are significantly higher with respect to those obtained in adults: for atrial membranes, Kd = 22.2 +/- 9.7 and 11.6 +/- 1.8 pM; Bmax = 58.4 +/- 22.8 and 42.1 +/- 8.9 fmol/mg protein, respectively in explanted hearts and in post mortem specimens. No significant differences have been found in the binding parameters between infants and children, while, considering our results as a whole, a significant inverse correlation between Bmax and subject age (p<0.001) is suggested. The ET-A/ET-B ratio, evaluated by competition experiments with the specific ET-A antagonist BQ-123, was about 70:30 in pediatric patients, in both atrium and ventricle, without any difference between infants and children. Similar values for ET-A/ET-B ratio in adult CHF patients, in contrast to a reduction (significant only in ventricle) of the percent of ET-A subtype in autopsy, has been found. This is the first study concerning a direct evaluation of ET receptor status in children's hearts; the higher density of binding sites, associated to the elevation of plasma levels, could suggest a enhanced biological function of ET in children.

Acute histologic and ultrastructural study in one case of human basilar tip aneurysm embolised with guglielmi detachable coils.

SUMMARY: Histologic findings after Guglielmi detachable coils endovascular embolisation have been studied in experimental aneurysms. Few reports describe histopathologic reactions to platinum coils in humans. In this report we describe gross, light microscopic pathology and scanning electron microscopy study of a ruptured basilar tip artery aneurysm in a patient who died 16 hours following coiling.

FHIT and p53 gene abnormalities in bronchioloalveolar carcinomas. Correlations with clinicopathological data and K-ras mutations.

Bronchioloalveolar carcinoma (BAC) is a particular type of adenocarcinoma of the lung which accounts for up to 9 per cent of pulmonary malignancies. The aetiology and pathogenesis of this unique neoplastic disease are still unclear. Three histological subtypes of BAC have been recognized: mucinous, non-mucinous, and sclerosing. Of these, mucinous and sclerosing BAC have a worse prognosis than non-mucinous tumours. The different morphological patterns and clinical outcomes of the subtypes of BAC suggest differences in their biological behaviour. Previous reports have shown that the mucinous form of BAC is characterized by constant mutations at codon 12 of the K-ras gene, whereas the other two histotypes show a frequency of K-ras mutations which is not different from that observed in conventional lung adenocarcinomas. The present study of a series of 51 BACs, previously investigated for K-ras gene mutations, has evaluated the status of two other genes, p53 and FHIT, known to be frequently altered in non-small cell lung cancer. Loss of heterozygosity at microsatellite-containing loci located within the FHIT gene was observed in 22 (43 per cent) BACs. The distribution of FHIT gene abnormalities was not statistically different in the three histological subtypes. p53 mutations were present in 13 (32 per cent) non-mucinous/sclerosing BACs, while no mutations were seen in mucinous tumours (P = 0.039). Correlations with clinicopathological parameters showed that p53 mutations in BACs are associated with more aggressive tumours. No correlations were observed between FHIT or K-ras gene abnormalities and clinicopathological data. In conclusion, these results indicate that FHIT alterations are frequently involved in BAC tumourigenesis and that genetic changes in the p53 and K-ras genes can distinguish between different histotypes of BAC.

Presence of endothelin-1 in the normal and pathological human thyroid.

An immunohistochemical study with two rabbit polyclonal antibodies I-AR76 and CA-08-351 against Endothelin-1 (ET-1) was performed in 133 human thyroid specimens: 5 normal thyroids, 30 multinodular goiters (15 toxic and 15 nontoxic), 20 Graves' diseases, 5 Hashimoto's thyroiditis, 26 adenomas (6 Hürthle cell, 16 toxic and 4 nontoxic), 30 classic papillary carcinomas, 3 minimally invasive follicular carcinomas, 1 widely invasive follicular carcinoma, 3 undifferentiated carcinomas and 10 medullary carcinoma. All normal thyroids, non toxic multinodular goiters and non toxic adenomas, 4 (66%) Hürthle cell adenomas, 3 (15%) Graves' diseases, 1 (33%) case of minimally invasive follicular carcinoma showed rare follicular cells with weak cytoplasmic immunoreactivity. Many immunoreactive follicular cells, with or without oxyphilic changes, were observed in all specimens of Hashimoto's disease, while the lymphocytic infiltrate was always negative. Twenty-seven (90%) classic papillary carcinomas were positive. Immunoreactivity was intracytoplasmic, weak in 14 cases and intense in 13. The cells of toxic adenoma and toxic multinodular goiter were negative, whereas the acellular stroma was intensely positive in both cases. Medullary and undifferentiated carcinomas were negative. These results show ET-1 immunoreactivity in normal and pathological human thyroids. In particular, the high content of this peptide in the thyroid papillary carcinoma suggests that ET-1, whose mitogenic role has recently been emphasized, could be involved in the growth of this tumor.

Breast carcinoma with osteoclast-like giant cells: immunohistochemical and ultrastructural study of a case and review of the literature.

We describe an unusual case of infiltrating ductal carcinoma, not otherwise specified, containing numerous benign stromal osteoclast giant cells (OGCs). Macroscopically, the tumor appeared as a well-outlined dark brown mass and was initially interpreted as a benign lesion on the mammograms. OGCs were uniformly distributed in the tumor and were found in vascularized, hemorrhagic stroma often abutted on the nests of tumor cells. Electron microscopy supported a histiocytic origin of the OGCs, but immunohistochemistry failed to confirm the observation. The patient was alive and well 30 months following the operation. A review of the literature concerning breast carcinoma with OGCs is also presented.

[Etiopathogenesis of dilated cardiomyopathies]. / Eziopatogenesi delle cardiomiopatie dilatative.

This study was carried out on 43 patients affected by dilated cardiomyopathy to investigate some of the etiopathological hypotheses on this illness. The Authors investigated: the persistence of virus genoma (coxsackie, HBV) on endomyocardial biopsies; the pattern of the II class major histocompatibility complex (MHC) were in the blood lymphocytes; the microvascular aspect of coronary circulation in the endomyocardial biopsies. Finally, in a separated group of 19 patients, the microvascular circulation was studied on skin biopsies and correlated with diabetic, valvular and normal subject. The results showed a 14% positivity for the presence of the virus genoma and a significant predominate of DR5 in the II class MHC of patients with a worse ventricular function. Capillary vessels of the coronary microcirculation were dilated in the 48% of the patients, especially in more compromised subjects. Viral myocarditis seem to play a role in the etiopathogenesis of dilated cardiomyopathies (DCM) and the pattern of MHC could influence the progression of the illness. The microcirculation is probably a pathophysiological aspect. No etiological hypothesis seems to predominate.

[From myocardial hypertrophy to heart failure: role of the interstitium]. / Dall'ipertrofia miocardica allo scompenso cardiaco: ruolo dell'interstizio.

In the progression from myocardial hypertrophy to heart failure, abnormalities in the interstitial space of the heart seem to play a critical role. The formation of an extracellular oedema and the alterations in coronary subendocardial perfusion are associated with the development of interstitial fibrosis. Cardiac experimental studies documented the presence of augmented interstitial fluid volume and pressure and a subsequent remodelling of the fibrillar network of the extracellular space of the myocardium during the phases of the cardiovascular response to a sudden overload. Variations of the Starling's forces balance caused by enhanced endothelial permeability or due to an impairment of cardiac lymphatic drainage may contribute to the development of an acute heart failure. During stable hyperfunction, the organization of a chronic oedema should account for interstitial changes in the hypertrophic myocardium. Reactive fibrosis seems to be under hormonal control. The activation of the renin-angiotensin-aldosterone system is responsible for interfascicular and intercellular accumulation of fibrillar collagen within the cardiac interstitium. Perivascular fibrosis in the subendocardium may impair intramyocardial distribution of coronary flow. When an inadequate hypertrophy occurs, because of an elevation in ventricular wall stress, myocardial oxygen consumption rises and this may lead to the exhaustion of coronary blood flow reserve in the subendocardial layers. This underperfusion may be responsible for the development of myocardial ischemia. Coronary hemodynamic changes in the microcirculation as those prompted by interstitial alterations may contribute to the onset of myocyte necrosis and to the formation of restorative fibrosis. The progressive mechanical overload of the spared hypertrophied myocytes could explain the initiation of a positive feedback mechanism which perpetuates endomyocardial perfusion impairment, interstitial oedema and remodelling, finally, causing myocyte deaths and fibrous tissue proliferation. These structural alterations and their pathophysiological counterparts appear to be closely related to the evolution from compensatory hypertrophy to chronic myocardial failure in hypertrophic heart disease.

Multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis: description of a new family.

Multiple endocrine neoplasia (MEN) 2A associated to cutaneous lichen amyloidosis is a variant of MEN 2A recently reported in few families. We describe an additional family with this syndrome. The skin lesion is a pruritic one, located over the upper back showing, at biopsy, cutaneous amyloid. The propositus of our family was a 35-year-old woman already treated with total thyroidectomy for medullary thyroid cancer and with bilateral adrenalectomy for pheochromocytoma. The patient referred that the skin lesion was present since childhood and increased with time. Skin biopsy showed negative staining for amyloid, for calcitonin and neuron-specific enolase. The paraspinal muscles corresponding to the area of affected skin showed slight neurogenic abnormalities. Ten other members of her family were affected by MEN 2A, three of whom (all females) had the same cutaneous alteration.

3'-Deamino-3'-(2-methoxy-4-morpholinyl)-doxorubicin (FCE 23762): a new anthracycline derivative with enhanced cytotoxicity and reduced cardiotoxicity.

The purpose of this study was to examine the cytotoxicity and cardiotoxicity of the new doxorubicin derivative, 3'-deamino-3'-(2-methoxy-4-morpholinyl)-doxorubicin (FEC 23762). The concentration of FCE 23762 that resulted in a 50% reduction in colony formation of DU 145, COLO 320DM, A549 and A2780 human cancer cell lines ranged from 1.1 and 3.2 nmol/l and was 3-9 times as low as doxorubicin. In the isolated perfused rat hearts, doxorubicin 10(-5) mol/l induced a significant prolongation of S alpha T segment and Q-Fmax interval, and reduction in dF/dtmax and coronary flow while only FCE 23762 10(-5) mol/l induced a widening of QRS complex. Anaesthetised rats given a single intravenous (i.v.) dose of doxorubicin 10 mg/kg showed significant changes in both ECG (S alpha T segment and QRS complex enlargement) and haemodynamic parameters (increase in mean arterial blood pressure and reduction in systemic arterial dP/dtmax), while animals given FCE 23762 (0.1 and 0.3 mg/kg) had a significant increase in QRS complex duration after the highest dose. In the chronic cardiotoxicity study animals receiving FCE 23762 (0.03 mg/kg i.v. once a week for 3 weeks) did not show any significant alteration of ECG and minor changes of cardiac histological picture; by contrast doxorubicin (3 mg/kg i.v. once a week for 3 weeks) induced a severe cardiomyopathy, characterised by progressive widening of S alpha T segment, increase in T wave and histological damage consisting of vacuolations and loss of myofibrils. These results indicate that FCE 23762 is more active in vitro than doxorubicin and markedly less cardiotoxic in vivo at the doses used in the present study.