Molecular basis of heart failure and dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure. Several prospective studies have shown that about 25-30% of all cases are of familial etiology. The most common mode of inheritance is autosomal dominant. Less frequently is inheritance as an X-chromosomal trait. Examination of families has identified nine disease genes so far. The penetrance of the identified mutations is highly variable and age-dependent. Many relatives of patients with DCM show only minor cardiac abnormalities, and it is unknown whether they progress to full cardiomyopathy in later life. Knowledge of the DCM disease genes led to the new hypothesis that DCM is a disease of myocardial generation or transmission of force. Better understanding of the expression and function of disease genes may lead to new diagnostic and therapeutic tools.     

Laparoscopic treatment of acute cholecystitis. Incidence of anatomo-clinical variations (271 cases)

The study is based on 1050 laparoscopic cholecystectomies for gallstones performed between 1991-1999, out of which 271 were preoperatively considered as acute cholecystitis (25.8%). The clinical, biological and ultrasound criteria were rigorously respected. The preoperative period of 1 to 5 days (mean--2.5) was used for re-equilibration and antibiotic and antithrombotic therapy. The intraoperative criteria were clinical, echolaparoscopical, cholangiographical and bacteriological and established in 219 cases the diagnostic of acute cholecystitis. The final diagnostic, on histopathological basis, confirmed the preoperative diagnosis of acute cholecystitis in 224 cases. The microscopical reexamination in the remainding controversy cases reclassified other 18 as acute cholecystitis (final concordance ratio--242:271). The preoperative overvaluation may be consecutive to a too rapid (before the constitution of specific lesions) or too delayed intervention (the aspect becoming chronical). The elements of diagnostic discordance are raising the problem of case selection and the necessity for standard classification of histological lesions in acute cholecystitis.     

Successful closure of postpneumonectomy bronchopleural fistulae by latissimus dorsi island flap and closed-chest irrigation

Bronchopleural fistula after pneumonectomy is a dreaded complication, because of its high morbidity and mortality. We describe a successful technique using closed-chest irrigation of the pleural cavity continued with transposition of a latissimus dorsi island flap.     

A new Mr 55,000 surface protein implicated in melanoma progression: association with a metastatic phenotype

Emergence of the invasive phenotype is a key event in the progression of human melanoma from benign proliferative lesions to malignant lesions. Recently we successfully selected in vivo from a poorly metastatic M4Beu. human melanoma cell line two variants (7GP and T1P26) that generate a higher frequency of spontaneous metastases to the lungs into immune-suppressed neonatal rats. Both cell lines showed no significant differences in the integrin profile of the subunits analyzed except for beta3, which was reduced to a background level in metastatic variants. To investigate how these variant sublines of human melanomas manage to sustain growth in the absence of alpha(v)beta3, a subtractive immunization approach was used to elicit host antibody response against cell surface proteins expressed on metastatic variants. In this study, a new monoclonal antibody (MoAb), LY1, that is highly specific for the 7GP and T1P26 variants, was isolated. LY1 identifies a membrane protein of Mr 55,000 on melanoma variants with epitopes that were resistant to sugar-cleaving enzymes. Immunostaining cells from variants by LY1 showed that staining is distributed to the cell periphery with high labeling intensity at the cell-to-cell contact points. This MoAb significantly inhibited invasion of metastatic variants through a reconstituted basement membrane (Matrigel) in vitro. Moreover, tumor growth of melanoma variants was dramatically affected in vivo with this MoAb. In vitro studies indicate that the LY1 MoAb does not inhibit chemotactic migration of the metastatic variants, the adhesion of tumor cells to vitronectin, collagen IV, fibronectin, and laminin, or cell proliferation. Expression of this antigen is high in human striated muscle, heart, spleen, brain, and lung and absent in kidney, liver, and pancreas. Using 59 fixed, paraffin-embedded archival tissues of human melanomas and nevi, LY1-reactive cells were not observed in melanocytes, nevi, or radial growth phase primary melanomas. In sharp contrast, LY1 selectively stained melanocytes derived from the vertical growth phase of many primary melanomas and metastatic melanomas. These results provide evidence that the Mr 55,000 protein expressed by selected variants with increased metastatic properties in vivo plays a functionally important role in determining metastasis. This molecule may represent a new metastatic risk marker in human melanoma and may be of biological importance in the identification of fatal metastatic subpopulations that have acquired competence for metastasis production.     

A propos des résultats d’une enquête anonyme portant sur les relations entre les rhumatologues et les centres anti-douleurs

Conclusions  Finalement, il existe un véritable contraste entre l’attente des rhumatologues quand ils adressent des patients aux Centres pensant qu’ils sont utiles pour la majorité d’entre eux et l’impression finale: soit les Centres sont inutiles, soit ils révèlent une méconnaissance de la Rhumatologie et du r?le des rhumatologues. Pourtant, ces derniers semblent prêts à faire bénéficier ces Centres de leur expérience. Si ce questionnaire permet de mieux préciser la relation des rhumatologues avec les Centres de la Douleur, il souligne la nécessité pour ces mêmes Centres de mieux faire conna^itre leurs pratiques et leurs indications. Une collaboration entre les médecins des Centres et leurs homologues libéraux doit être renforcée, de même qu’une implication plus active des rhumatologues dans ces Centres serait nécessaire pour améliorer la prise en charge des patients douloureux chroniques, en particulier en Rhumatologie.     

Porphyria cutanea tarda-like dermatosis by hemodialysis

Summary The authors studied by electron microscope, the sun-exposed skin of the back of the hand from three heavily hemodialysed patients with a porphyria cutanea tarda-like bullous skin disease.The vascular impairment, like that of PCT, closely resembles that seen during medicamentous phototoxic processes. The connective tissue is infiltrated by large granulo-filamentous masses and the fibroblasts are secretory in appearance. At the dermal-epidermal junction, the abnormalities are important, with a diffuse infiltration of the upper dermis by a hyalin substance, probably resulting in a collagen degeneration and cellular necrosis.The aetiological factors are uncertain, as no common medicamentous factor appeared in our patients, and as the plasticizers used in the hemodialysis tubes probably played no part.

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Zusammenfassung Die sonnenexponierte Haut der Handrücken von drei Hämodialysepatienten mit einer Porphyria cutanea tarda-ähnlichen Dermatose wurde elektronenmikroskopisch untersucht. Die Gefäßveränderungen entsprechen denen, die während eines medikamentösen phototoxischen Prozesses mit PCT beobachtet werden.Das Bindegewebe ist mit granulo-filamentösem Material infiltriert und die Fibroblasten befinden sich im aktivierten sekretorischen Zustand. Im Bereiche der dermal-epidermalen Grenzzone sind diese Veränderungen besonders ausgeprägt, wobei eine diffuse Infiltration der oberen Dermis mit einer Hyalinsubstanz — offenbar das Resultat einer Kollagendegeneration — und einer cellulären Nekrose vorliegt.Die ätiologischen Faktoren sind ungewiß, da keine besonderen Medikamente bei den Patienten gegeben wurden und das Kunststoffmaterial, welches bei den Hämodialysegeräten verwandt wird, wohl keine Rolle spielt.

     

Effects of clonidine, prazosin and phentolamine on heart rate and coronary sinus catecholamine concentration during cardioaccelerator nerve stimulation in spinal dogs

1 In spinal dogs, continuous electrical stimulation of the cardioaccelerator nerve produced a transient rise in aortic blood pressure and a sustained increase in both heart rate and coronary sinus blood flow. The latter effects were accompanied by a significant elevation in the coronary sinus plasma noradrenaline concentration without significant changes in the levels of dopamine and adrenaline. The concentrations of the three catecholamines in thoracic aorta plasma were not significantly changed by cardioaccelerator nerve stimulation.

2 Clonidine (20 μg/kg, i.v.), given during cardioaccelerator nerve stimulation, increased both mean aortic blood pressure and coronary sinus blood flow and decreased heart rate and coronary sinus venous plasma noradrenaline overflow.

3 Phentolamine (0.3 mg/kg, i.v.) completely antagonized these effects of clonidine. Prazosin (0.3 mg/kg, i.v.) inhibited by only 43 and 38% the respective reductions in heart rate and noradrenaline overflow elicited by clonidine.

4 On termination of cardioaccelerator stimulation (about 10 min after either prazosin or phentolamine), heart rate and coronary sinus noradrenaline overflow returned to control prestimulation levels.

5 Phentolamine or prazosin, administered alone during stimulation of the cardioaccelerator nerve, increased heart rate and noradrenaline overflow into the coronary sinus plasma. However, intravenous phentolamine and prazosin, in contrast to desipramine (0.3 mg/kg, i.v.) or tyramine (1.0 mg, i.a.), failed to change the tachycardia resulting from the local administration of noradrenaline into the sinus node artery (i.a.).

6 These results show that in spinal dogs the clonidine-induced reduction in heart rate (elevated by electrical stimulation of the cardioaccelerator nerve) is accompanied by a fall in the quantity of noradrenaline overflowing into the coronary sinus plasma. The latter effect is presumably the result of an action of clonidine on cardiac presynaptic α-adrenoceptors, the activation of which is followed by a reduction in the release of noradrenaline per nerve impulse. Phentolamine and prazosin are both antagonists of cardiac presynaptic α-adrenoceptors in spinal dogs, as suggested by their action against clonidine and by their positive chronotropic effect when administered during stimulation of the cardioaccelerator nerve.

     

Independent ventilation of the graft and native lungs in vivo after rat lung transplantation

Rat lung transplantation is a proven experimental technique for the study of lung injury following lung transplantation. We have modified the surgical and ventilatory techniques to allow for independent ventilation in vivo of the transplanted graft and native lungs. This will provide additional data on the physiology and function of the transplanted graft and ameliorate the problem of progressive graft lung collapse and thereby allow for an improved model of ischemia-reperfusion injury and ventilator-induced lung injury in the setting of lung transplantation.     

Regulatory role of host CD8+ T lymphocytes in experimental graft-versus-host disease across a single major histocompatibility complex class II incompatibility

BACKGROUND: CD8+ T cells are known to regulate type 2 helper T cell (Th2) alloreactive immune responses but their mode of activation is unclear. We investigated the role of host CD8+ T cells in experimental Th2-type graft-versus-host disease (GVHD) where donor/recipient disparity is restricted to a single major histocompatibility complex (MHC) class II antigen. METHODS: Immunoglobulin (Ig) E serum levels, eosinophilia and lymphoid tissue hyperplasia were compared after injection of bm12 CD4+ T cells in either wild-type or CD8+ T cell-deficient (CD8-/-) C57BL/6 mice. In vitro, we explored effects of the addition of CD8+ T cells from wild-type or IFN-gamma-/- mice in mixed leukocyte cultures prepared with beta2 microglobulin-deficient (beta2m-/-) CD4+ T cells as responders or beta2m dendritic cells as stimulators. RESULTS: HyperIgE resolved after 3 weeks in wild-type hosts whereas it persisted for 6 weeks in CD8-/- hosts. Eosinophil infiltrates in lymph nodes were significantly enhanced in CD8-/- hosts. Increased serum levels of IL-5 and IL-13 in CD8-/- hosts confirmed the enhancement of Th2-type responses in the context of recipient CD8+ T cell deficiency. Hyperplasia of lymph nodes and spleen were similar in both groups, as well as in vivo proliferation of donor CD4+ T cells. In vitro, CD8+ T cell regulation of the alloreactive Th2 response depended on their production of IFN-gamma and did not require expression of beta2m on CD4+ T cells or antigen-presenting cells. CONCLUSIONS: Host CD8+ T cells regulate alloreactive Th2 responses during graft-versus-host disease through an IFN-gamma dependent pathway, independently of the recognition of beta2m-associated MHC class I molecules.