Estudos sobre thrombose cardiaca e endocardite parietal de origem não valvular

1.-Since the parietal endocarditis represents a chapter generally neglected, owing to the relative lack of cases, and somewhat confused because there various terms have been applied to a very same morbid condition, it justifies the work which previously we tried to accomplish, of nosographic classification. Taking into account the functional disturbances and the anatomical changes, all cases of parietal endocarditis referred to in the litterature were distributed by the following groups: A-Group-Valvulo-parietal endocarditis. 1st . type-Valvulo-parietal endocarditis per continuum. 2nd. type-Metastatic valvulo-parietal endocarditis. 3rd. type-Valvulo-parietal endocarditis of the mitral stenosis. B-Group-Genuine parietal endocarditis. a) with primary lesions in the myocardium. b) with primary lesions in the endocardium. 4th type-Fibrous chronic parietal endocarditis (B A Ü M L E R), « endocarditis parietalis simplex». 5th type-Septic acute parietal endocarditis (LESCHKE), «endocarditis parietalis septica». 6th type-Subacute parietal endocarditis (MAGARINOS TORRES), «endocarditis muralis lenta». 2.-Studying a group of 14 cases of fibrous endomyocarditis with formation of thrombi, and carrying together pathological and bacteriological examinations it has been found that some of such cases represent an infectious parietal endocarditis, sometimes post-puerperal, of subacute or slow course, the endocardic vegetations being contamined by pathogenic microörganisms of which the most frequent is the Diplococcus pneumoniae, in most cases of attenuated virulence. Along with the infectious parietal endocarditis, there occur arterial and venous thromboses (abdominal aorta, common illiac and femural arteries and external jugular veins). The case 5,120 is a typical one of this condition which we name subacute parietal endocarditis (endocarditis parietalis s. muralis lenta). 3.-The endocarditis muralis lenta encloses an affection reputed to be of rare occurrence, the «myocardite subaigüe primitive», of which JOSSERAND and GALLAVARDIN published in 1901 the first cases, and ROQUE and LEVY, another, in 1914. The «myocardite subaigüe primitive» was, wrongly, in our opinion, included by WALZER in the syndrome of myocardia of LAUBRY and WALZER, considering that, in the refered cases of JOSSERAND and GALLAVARDIN and in that of ROQUE and LEVY, there are described rather considerable inflammatory changes in the myocardium and endocardium. The designation «myocardia» was however especially created by LAUBRY and WALZER for the cases of heart failure in which the most careful aetiologic inquiries and the most minucious clinical examination were unable to explain, and in which, yet, the post-mortem examination did not reveal any anatomical change at all, it being forcible to admit, then, a primary functional change of the cardiac muscle fibre. This special cardiac condition is thoroughly exemplified in the observation that WALZER reproduces on pages 1 to 7 of his book. 4.-The clinical picture of the subacute parietal endocarditis is that of heart failure with oedemas, effusion in the serous cavities and passive chronic congestion of the lungs, liver, kideys and spleen associated, to that of an infectious disease of subacute course. The fever is rather transient oscillating around 99.5 F., being intersected with apyretic periods of irregular duration; it is not dependent on any evident extracardiac septic infection. In other cases the fever is slight, particularly in the final stage of the disease, when the heart failure is well established. The rule is to observe then, hypothermy. The cardiac-vascular signs consist of enlargement of the cardiac dullness, smoothing of the cardiac sounds, absence of organic murmurs and accentuated and persistent tachycardia up to a certain point independent of fever. The galloprhythm is present, in most cases. The signs of the pulmonary infarct are rather expressed by the aspect of the sputum, which is foamy and blood-streaked than by the classic signs. Cerebral embolism was a terminal accident on various cases. Yet, in some of them, along with the signs of septicemia and of cardiac insufficiency, occurred vascular, arterial (abdominal aorta, common illiac and femurals arteries) and venous (extern jugular veins) thromboses. 5. The autopsy revealed an inflammatory process located on the parietal endocardium, accompanied by abundant formation of ancient and recent thrombi, being the apex of the left ventricle, the junction of the anterior wall of the same ventricle, with the interventricular septum, and the right auricular appendage, the usual seats of the inflammatory changes. The region of the left branch of HIS’ bundle is spared. The other changes found consist of fibrosis of the myocardium (healed infarcts and circumscribed interstitial myocarditis), of recent visceral infarcts chiefly in lungs, spleen and brain, of recent or old infarcts in the kidneys (embolic nephrocirrhosis) and in the spleen, and of vascular thromboses (abdominal aorta, common illiacs and femurals arteries and external jugular veins), aside from hydrothorax, hydroperitoneum, cutaneous oedema, chronic passive congestion of the liver, lungs, spleen and kidneys and slight ictericia. 6. In the subacute parietal endocarditis the primary lesions sometimes locate themselves at the myocardium, depending on the ischemic necrosis associated to the arteriosclerosis of the coronariae arteries, or on an specific myocarditis. Other times, the absence of these conditions is suggestive of a primary attack to the parietal endocardium which is then the primary seat of the lesions. It matters little whatever may be the initial pathogenic mechanism; once injured the parietal endocardium and there being settled the infectious injury, the endocarditis develops with peculiar clinical and anatomical characters of remarkable uniformity, constituting an anatomo-clinical syndrome. 7.-The histologic sections show that recent lesions…

Sobre os efeitos vasomotôres exercidos pela agua distilada e pelas soluções anisotonicas de clorêto de sodio

The writer reports experiments done with distilled water and hypotonic and hypertonic salt solutions of definite osmotic concentrations. The experiments were performed according to the Laewen-Trendelenburg technic using the vascular system of the frog's hind legs, and according to the Pissemski-Krawkow method using the capillaries of the rabbit's ear. Both preparations react to distilled water by marked vaso-constriction, the same phenomenon taking place in the case of the hypotonic salt solutions. The lower the concentration pf the hypotonic salt solution the stronger the vaso-constriction obtained. With hypertonic salt solutions was observed a strong but rather transient vaso-dilatation followed by secondary vaso-constriction. The later results were found only in the experiments with the frog's hind legs.

Alterações cutâneas do cão no Kala-Azar sul-americano

According to E. Chagas (1938), South-American Kala Azar is a widespread disease from the jungle, several cases being reported from North Brazil (Estado do Pará: Marajó Island, Tocantins and Gurupi river valleys; Estados do Piauí and Ceará: coast and hinterland). Other cases were found in Northeast Brazil (Estados de Pernambuco, Alagôas and Sergipe: coast and hinterland; Estado da Bahia: hinterland). A few cases were described from Estado de Mato-Grosso (Brazil), Provincia de Salta and Território do Chaco (Argentine), and Zona contestada do Chaco (Paraguai-Bolívia). A well defined secondary anemia associated with enlargement of the liver and spleen are the chief symptoms. Death usually occurs in cachexia and with symptoms of heart failure. Half the patients were children aged less than ten years (CHAGAS, CASTRO & FERREIRA, 1937). Quite exhaustive epidemiological researches performed by CHAGAS, FERREIRA, DEANE, DEANE & GUIMARÃES (1938) in Municipio de Abaeté (Estado do Pará, Brazil) gave the incidence of 1.48% for the natural infection in human, 4.49% in dogs, and 2.63% in cats. The infection was arcribed (CUNHA & CHAGAS, 1937) to a new species of Leishmania (L. chagasi). Latter CUNHA (1938) state, that it is identical to L. infantum. ADLER (1940) found that so far it has been impossible to distinguish L. chagasi from L. infantum by any laboratory test but a final judgment must be reserved until further experiments with different species of sandflies have been carried out. Skin changes in canine Kala Azar were signaled by many workers, and their importance as regards the transmission of the disease is recognized by some of them (ADLER & THEODOR, 1931, 2. CUNHA, 1933). Cutaneous ulcers in naturally infected dogs are referred by CRITIEN (1911) in Malta, by CHODUKIN & SCHEVTSCHENKO (1928) in Taschkent, by DONATIEN & LESTOCQUARD (1929) and by LESTOCQUARD & PARROT (1929) in Algeria, and by BLANC & CAMINOPETROS (1931) in Greece. Depilation is signaled by YAKIMOFF & KOHL-YAKIMOFF (1911) in Tunis, by YAKIMOFF (1915) in Turkestan. Eczematous areas or a condition described as "eczema furfurace" is sometimes noted in the areas of depilation (DONATIEN & LESTOCQUARD). The skin changes noticed by ADLER & THEODOR (1932) in dogs naturally infected with Mediterranean Kala Azar can be briefly summarized as a selective infiltration of macrophages around hair follicles including the sebaceous glands and the presence of infected macrophages in normal dermis. The latter phenomenon in the complete absence of secondary infiltration of round cells and plasma cells is the most striking characteristic of canine Kala Azar and differentiates it from L. tropica. In the more advanced stages the dermis is more cellular than that of normal dogs and may even contain a few small dense areas of infiltration with macrophages and some round cells and polymorphs. The external changes, i. e., seborrhea and depilation are roughly proportional to the number of affected hair follicles. In dogs experimentally infected with South-American Kala Azar the parasites were regularly found in blocks of skin removed from the living animal every fortnight (CUNHA, 1938). The changes noticed by CUNHA, besides the presence of Leishmania, were perivascular and diffuse infiltration of the cutis with mononuclears sometimes more marked near hair follicles, as well as depilation, seborrhea and ulceration. The parasites were first discovered and very numerous in the paws. Our material was obtained from dogs experimentally infected by Dr. A. MARQUES DA CUNHA< and they were the subject of a previous paper by CUNHA (1938). In this study, however, several animals were discarded as it was found that they did develop a superimposed infection by Demodex canis. This paper deals with the changes found in 88 blocks of skin removed from five dogs, two infected with two different canine strains, and three with two distinct human strains of South-American Kala Azar. CUNHA'S valuable material affords serial observations of the cutaneous changes in Kala Azar as most of the blocks of skin were taken every fortnight. The following conclusions were drawn after a careful microscopic study. (1) Skin changes directly induced in the dog by the parasites of South-American Kala Azar may b described as an infiltration of the corium (pars papillaris and upper portion of the reticular layer) by histocytes. Parasites are scanty, at first, latter becoming very numerous in the cytoplasm of such cells. Sometimes the histocytes either embedding or not leishman bodies appear as distinct nodes of infiltration or cell aggregations (histocytic granuloma, Figs. 8 and 22) having a perivascular distribution. The capillary loops in the papillae, the vessels of the sweat glands, the subpapillary plexus, the vertical twigs connecting the superficial and deep plexuses are the ordinary seats of the histocytic Kala Azar granulomata. (2) Some of the cutaneous changes are transient, and show spontaneous tendency to heal. A gradual transformation of the histocytes either containing or not leishman bodies into fixed connective tissue cells or fibroblasts occut and accounts for the natural regression just mentioned. Figs. 3, 5, 18, 19 and 20 are good illustrations of such fibroblastic transformation of the histocytic Kala Azar granulomata. (3) Skin changes induced by the causative organism of South-American Kala Azar are neither uniform nor simultaneous. The same stage may be found in the same dog in different periods of the disease, and not the same changes take place when pieces from several regions are examined in the same moment. The fibroblastic transformation of the histocytic granulomata marking the beginning of the process of repair, e. g., was recognised in dog C, in the 196th as well as in the 213rd (Fig. 18) and 231st (Fig. 19) days after the inoculation. (4) The connective tissue of the skin in dogs experimentally infected with South-American Kala Azar is overflowed by blood cells (monocytes and lymphocytes) besides the proliferation in situ of undifferentiated mesenchymal cells. A marked increase in the number of cells specially the "ruhende Wanderzellen" (Figs. 4 and 15) is noticed even during the first weeks after inoculation (prodomal stage) when no leishman bodies are yet found in the skin. Latter a massive infiltration by amoeboid wandering cells similar to typical blood monocytes (Fig. 21) associated to a small number of lymphocytes and plasma cells (Figs. 9, 17, 21, and 24) indicates that the emigration of blood cells...

Features of reproduction in laboratory-reared Aedes fluviatilis (Lutz, 1904) (Diptera: Culicidae)

Observations were made on 100 female Aedes fluviatilis (Lutz) maintained individually from the first blood meal onwards and allowed one blood meal during each oviposition cycle, 5% dextrose solution been supplied throughout life. The average length of live was 49.9 ± 17.8 days; the logarithm of the mortality rate increased proportionately to physiological age. The insects took an average of 7.3 ± 3.2 blood meals and produced a mean of 7.9 ± 3.7 clutches of eggs. There was a progressive decrease, proportional to advancing physiological age, in the mean numbers of eggs laid in successive oviposition cycles, in the intervals between blood feeding oviposition, and in the numbers of larvae that hatched. Delayed oviposition, transient sterility and a total loss of fertility were also recorded.

Interleukin- 2 production during murine infection by Leishmania mexicana amazonensis

Highly susceptible BALB/c mice, resistant C57B1/6 and their F1 progeny (BDF1) were infected subcutaneously in the foot pad with Leishmania mexicana amazonenesis. At various times after infection, spleen or draining popliteal lymph node cells were assayed for their capacity to generate Interleukin-2 (I1-2) by Concanavalin A (ConA) stimulation. In both BALB/c and C57B1/6 strains there was a transient increase in their capacity to produce I1-2, from the 3rd to the 10th week post-infection. Return to pre-infection levels ocurred between 13th to 16th week post-infection in all three strains. BALB/c mice always produced higher titers of 11-2 than C57B1/6, but such differences were statistically significant only at 3 and 10 weeks post-infection. BDF1 mice had titers similar to those observed in BALB/c mice. I1-2 production by ConA-stimulated lymph node cells was lower as compared to the spleen, but with a similar pattern among the three mice strains. Our data show that susceptibility to infection by l. mexicana amazonenesis is not associated with deficient ConA-stimulated I1-2 production.

Subclinical femoral neuropathy after anterior cruciate ligament reconstruction

Background and aim of the study: Patients with anterior cruciate ligament (ACL) reconstruction and femoral catheter analgesia may develop quadriceps amyotrophy. We aimed to determine whether this amyotrophy might be related to a femoral neuropathy. Material and method: After Ethical Committee approval and patients' written informed consent, 17 patients ASA I and II scheduled to undergo ACL reconstruction were recruited. An electromyography (EMG) was performed before the operation in order to exclude a femoral neuropathy. A femoral nerve catheter was inserted before the surgery with the aid of a nerve stimulator, and 20 ml of 0.5% ropivacaine was injected. The operation was done under spinal or general anaesthesia. Postoperative analgesia was provided with 0.2% ropivacaine for 72 hours, in association with oxycodone, paracetamol and ibuprofen. A second EMG was performed 4 weeks after the ACL repair. A femoral neuropathy was defined as a reduction of the surface of the motor response of more than 20%, compared to the first EMG. A third EMG was performed at 6 months if a neuropathy was present. Results: Mean age of this group of patients was 27 years old (range 18-38 y.). Among the 17 patients, 4 developed a transient femoral neuropathy (incidence of 24%) without clinical complain. Conclusion: In this study, the incidence of subclinical femoral neuropathy after ACL reconstruction is high. This lesion may be caused by the femoral catheter (mechanical damage, toxicity of local anaesthesia) or by the Tourniquet. Further studies are needed to investigate the incidence of subclinical neuropathy, according to the type of analgesia (epidural analgesia, PCA) and surgery.

Prevention of bone marrow graft failure by an anti LFA-1 monoclonal antibody

Graft rejection is the major cause of failure of HLA mismatched bone marrow transplantation because of residual host immunity. we have proposed to use a monoclonal murine antibody specific for the LFA-1 molecule (25-3) to prevent graft failure in HLA mismatched bone marrow transplantation (BMT). The rationale for this approach is three fold: LFA-1 deficient patients (3/3) do not reject HLA mismatched BMT; anti LFA-1 blocka in vitro the induction of T cell responses and T/ non T cytotoxic functions; LFA-1 is not expressed by other cells than leucocytes. We have accordingly treated twenty two patients with inherited diseases and 8 with leikemia. The bone marrow was T cells depled by E rosetting of Campath antibody. The antibody was given at days -3, -1, +1, +3, +5 at dose of .1 mg/kg/d for the first 9 and then .2mg/kg/d from day -3 to +6. Engraftment occured in 23/30 patients as shown by at least HLA typing. Hematological recovery was rapid, GVH was limited. Side effects of antibody infusion included fever and possibly an increased incidence of early bacteral infection (sepsis, 1 death). Immunological reconstitution occured slowly leading in six cases to EBV-induced B cell poliferation (1 death and in two others to transient auto immune hemolytic anemia. There has been only one secondary graft rejection. Sisteen patients are alive 3 to 26 months post transplant with functional grafts. Although the number of patients treated is still low the absence of late rejection so far, gives hope for long term maintenance of the graft using anti LFA-1. Since the antibody is an IgG 1 unable to bind human complement, and since it is known to inhibit phagocytosis, there is a good suggestion that 25-3 act through functional blocking of host T and non T luymphocytes at both induction and effector levels.

Remyelination in vitro following protein kinase C activator-induced demyelination.

In previous work we found that mezerein, a C kinase activator, as well as basic fibroblast growth factor (FGF-2) induce demyelination and partial oligodendrocyte dedifferentiation in highly differentiated aggregating brain cell cultures. Here we show that following protein kinase C activator-induced demyelination, effective remyelination occurs. We found that mezerein or FGF-2 caused a transient increase in DNA synthesis following a pronounced decrease of the myelin markers myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphohydrolase. Both oligodendrocytes and astrocytes were involved in this mitogenic response. Within 17 days after demyelination, myelin was restored to the level of the untreated controls. Transient mitotic activity was indispensable for remyelination. The present results suggest that myelinating oligodendrocytes retain the capacity to reenter the cell cycle, and that this plasticity is important for the regeneration of the oligodendrocyte lineage and remyelination. Although it cannot be excluded that a quiescent population of oligodendrocyte precursor cells was present in the aggregates and able to proliferate, differentiate and remyelinate, we could not find evidence supporting this view.

The role of the right parietal cortex in sound localization: a chronometric single pulse transcranial magnetic stimulation study.

Auditory spatial functions, including the ability to discriminate between the positions of nearby sound sources, are subserved by a large temporo-parieto-frontal network. With the aim of determining whether and when the parietal contribution is critical for auditory spatial discrimination, we applied single pulse transcranial magnetic stimulation on the right parietal cortex 20, 80, 90 and 150 ms post-stimulus onset while participants completed a two-alternative forced choice auditory spatial discrimination task in the left or right hemispace. Our results reveal that transient TMS disruption of right parietal activity impairs spatial discrimination when applied at 20 ms post-stimulus onset for sounds presented in the left (controlateral) hemispace and at 80 ms for sounds presented in the right hemispace. We interpret our finding in terms of a critical role for controlateral temporo-parietal cortices over initial stages of the building-up of auditory spatial representation and for a right hemispheric specialization in integrating the whole auditory space over subsequent, higher-order processing stages.

Strokes restricted to the insular cortex

Résumé: L'objectif de l'étude est de caractériser la manifestation clinique d'une atteinte vasculaire cérébrale ischémique aiguë limitée au cortex insulaire, région intrigante et méconnue du cerveau humain. Dans la pratique clinique, une atteinte vasculaire aiguë limitée à l'insula, sans compromission d'autres régions cérébrales, est exceptionnelle et sa manifestation clinique neurologique est souvent non reconnue. L'étude est focalisée sur quatre patients, inscrits dans le Lausanne Stroke Registry, présentant une nouvelle atteinte vasculaire cérébrale avec une lésion unique purement limitée au cortex insulaire, objectivée à l'aide de la résonance magnétique (IRM). L'étude a mis en évidence cinq manifestations cliniques principales : 1) Troubles de la sensibilité corporelle sont révélé chez trois patients avec une atteinte insulaire postérieure (deux avec un syndrome pseudothalamique, un avec un déficit à distribution partielle). 2) Un patient avec une lésion insulaire postérieure gauche présent des troubles du goût. 3) Un syndrome pseudovestibulaire avec vertiges non rotatoires, instabilité à la marche sans nystagmus, est mis en évidence chez trois patients avec une atteinte ischémique insulaire postérieure. 4) Un patient avec atteinte de l'insula postérieure droite présente des épisodes d'hypertension artérielle d'origine cryptique. 5) Des troubles neuropsychologiques tels qu'aphasie et dysarthrie sont détectés chez les patients avec une atteinte insulaire postérieure gauche, un épisode de somatoparaphrénie est rapporté avec une atteinte insulaire postérieure droite. En conclusion, les atteintes vasculaires cérébrales ischémiques aiguës limitées au cortex insulaire postérieur peuvent se manifester principalement avec un tableau clinique caractérisé par un syndrome pseudothalamique associé à une symptomatologie pseudovertigineuse. Les lésions insulaires postérieures peuvent se manifester avec une dysarthrie et des troubles du goût, une aphasie (gauche), une somatoparaphrénie et une dysfonction hypertensive (droite). L'étude n'a pas mis en évidence de dysphagie, reportée dans les atteintes insulaires antérieures. Abstract: Objective: To characterize clinically acute insular strokes from four patients with, a first ever acute stroke restricted to the insula on MRI. Methods: The authors studied the clinical presentation of four patients with a first ever acute stroke restricted to the insula on MRI. Results: The authors found five main groups of clinical presentations: 1) somatosensory deficits in three patients with posterior insular stroke (two with a transient pseudothalamic sensory syndrome, one with partial distribution); 2) gustatory disorder in a patient with left posterior insular infarct; 3) vestibular-like syndrome, with dizziness, gait instability, and tendency to fall, but no nystagmus, in three patients with posterior insular strokes; 4) cardiovascular disturbances, consisting of hypertensive episodes in a patient with a right posterior insular infarct; and 5) neuropsychological disorders, including aphasia (left posterior insula), dysarthria, and transient somatoparaphrenia (right posterior insula). Conclusion: Strokes restricted to the posterior insula may present with pseudothalamic sensory and vestibular-like syndromes as prominent clinical manifestations, but also dysarthria and aphasia (in left lesions), somatoparaphrenia (right lesions) and gustatory dysfunction and blood pressure with hypertensive episodes in right lesions; we did not find acute dysphagia reported in anterior, insular strokes.

Membrane potential dynamics of neocortical projection neurons driving target-specific signals.

Primary sensory cortex discriminates incoming sensory information and generates multiple processing streams toward other cortical areas. However, the underlying cellular mechanisms remain unknown. Here, by making whole-cell recordings in primary somatosensory barrel cortex (S1) of behaving mice, we show that S1 neurons projecting to primary motor cortex (M1) and those projecting to secondary somatosensory cortex (S2) have distinct intrinsic membrane properties and exhibit markedly different membrane potential dynamics during behavior. Passive tactile stimulation evoked faster and larger postsynaptic potentials (PSPs) in M1-projecting neurons, rapidly driving phasic action potential firing, well-suited for stimulus detection. Repetitive active touch evoked strongly depressing PSPs and only transient firing in M1-projecting neurons. In contrast, PSP summation allowed S2-projecting neurons to robustly signal sensory information accumulated during repetitive touch, useful for encoding object features. Thus, target-specific transformation of sensory-evoked synaptic potentials by S1 projection neurons generates functionally distinct output signals for sensorimotor coordination and sensory perception.

Aggregating Brain Cell Cultures as a Model to Study Ischaemia-induced Neurodegeneration.

Rotation-mediated aggregating brain cell cultures at two different maturational stages (DIV 11 and DIV 20) were subjected for 1 or 2 hours to ischaemic conditions by transient immobilization (arrest of media circulation). During recovery, cell damage was evaluated by measuring changes in cell type-specific enzyme activities and total protein content. It was found that in immature cultures (DIV 11), immobilization for 1 or 2 hours did not affect the parameters measured. By contrast, at DIV 20, ischaemic conditions for 1 hour caused a pronounced decrease in the activities of glutamic acid decarboxylase and choline acetyltransferase. A significant decrease in these neuron-specific enzyme activities was found at post-ischaemic days 1-14, indicating immediate and irreversible neuronal damage. The activity of the astrocyte-specific enzyme, glutamine synthetase, was significantly increased at 4 days post-treatment; equal to control values at 6 days; and significantly decreased at 14 days after the ischaemic insult. Immobilization of DIV 20 cultures for 2 hours caused a drastic reduction in all the parameters measured at post-ischaemic day 6. Generally, the ischaemic conditions appeared to be more detrimental to neurons than to astrocytes, and GABAergic neurons were more affected than cholinergic neurons.

Switch to Sirolimus-based immunosuppresion in stable renal transplant recipients

Purpose: Sirolimus (SRL) has been used to replace calcineurin inhibitors (CNI) for various indications including CNI-induced toxicity. The aim of this study was to evaluate the efficacy and safety of switching from CNI to SRL in stable renal transplant recipients (RTR) with low grade proteinuria (<1 g/24 h). Methods and materials: Between 2001 and 2007, 41 patients (20 females, 21 males; mean age 47 ± 13) were switched after a median time post-transplantation of 73.5 months (range 0.2-273.2 months). Indications for switch were CNI nephrotoxicity (39%), thrombotic micro-angiopathy (14.6%), post-transplantation cancer (24.4%), CNI neurotoxicity (7.4%), or others (14.6%). Mean follow-up after SRL switch was 23.8±16.3 months. Mean SRL dosage and through levels were 2.4 ± 1.1 mg/day and 8 ± 2.2 ug/l respectively. Immunosuppressive regiments were SRL + mycophenolate mofetil (MMF) (31.7%), SRL + MMF + prednisone (36.58%), SRL + prednisone (19.51%), SRL + Azathioprine (9.75%), or SRL alone (2.43%). Results: Mean creatinine decreased from 164 to 143 μmol/l (p <0.03), mean estimated glomerular filtration rate (eGFR) increased significantly from 50.13 to 55.01 ml/minute (p <0.00001), mean systolic and diastolic blood pressure decreased from 138 to 132 mm Hg (p <0.03) and from 83 to78 mm Hg (p <0.01), but mean proteinuria increased from 0.21 to 0.63 g/24 h (p <0.001). While mean total cholesterolemia didn't increased significantly from 5.09 to 5.56 mmol/l (p = 0.06). The main complications after SRL switch were dermatitis (19.5%), urinary tract infections (24.4%), ankle edema (13.3%), and transient oral ulcers (20%). Acute rejection after the switch occurred in 7.3% of patients (n = 3), and 2 acute rejections were successfully treated with corticosteroids and 1 did not respond to treatment (not related to switch). SRL had to be discontinued in 17% of patients (2 nephrotic syndromes, 2 severe edema, 1 acute rejection, 1 thrombotic micro-angiopathy, and 1 fever). Conclusion: In conclusion, we found that switching from CNI to SRL in stable RTR was safe and associated with a significant improvement of renal function and blood pressure. Known side-effects of SRL led to drug discontinuation in less than 20% of patients and the acute rejection rate was 7.3%. This experience underlines the importance of patient selection before switching to SRL, in particular regarding preswitch proteinuria.

Representation of motor habit in a sequence of repetitive reach and grasp movements performed by macaque monkeys: evidence for a contribution of the dorsolateral prefrontal cortex.

In the context of an autologous cell transplantation study, a unilateral biopsy of cortical tissue was surgically performed from the right dorsolateral prefrontal cortex (dlPFC) in two intact adult macaque monkeys (dlPFC lesioned group), together with the implantation of a chronic chamber providing access to the left motor cortex. Three other monkeys were subjected to the same chronic chamber implantation, but without dlPFC biopsy (control group). All monkeys were initially trained to perform sequential manual dexterity tasks, requiring precision grip. The motor performance and the prehension's sequence (temporal order to grasp pellets from different spatial locations) were analysed for each hand. Following the surgery, transient and moderate deficits of manual dexterity per se occurred in both groups, indicating that they were not due to the dlPFC lesion (most likely related to the recording chamber implantation and/or general anaesthesia/medication). In contrast, changes of motor habit were observed for the sequential order of grasping in the two monkeys with dlPFC lesion only. The changes were more prominent in the monkey subjected to the largest lesion, supporting the notion of a specific effect of the dlPFC lesion on the motor habit of the monkeys. These observations are reminiscent of previous studies using conditional tasks with delay that have proposed a specialization of the dlPFC for visuo-spatial working memory, except that this is in a different context of "free-will", non-conditional manual dexterity task, without a component of working memory.

Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells.

Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasome-dependent reduction of p21(WAF1/CIP1) and p27(KIP1) protein levels, whereas little or no effect was observed on p21(WAF1/CIP1) or p27(KIP1) mRNAs. p21(WAF1/CIP1) silencing also increased MCF-10A cell proliferation, thus identifying p21(WAF1/CIP1) down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.