Treatment of atrial fibrillation with radiofrequency ablation and simultaneous multipolar mapping of the pulmonary veins

OBJECTIVE: To demonstrate the feasibility and safety of simultaneous catheterization and mapping of the 4 pulmonary veins for ablation of atrial fibrillation. METHODS: Ten patients, 8 with paroxysmal atrial fibrillation and 2 with persistent atrial fibrillation, refractory to at least 2 antiarrhythmic drugs and without structural cardiopathy, were consecutively studied. Through the transseptal insertion of 2 long sheaths, 4 pulmonary veins were simultaneously catheterized with octapolar microcatheters. After identification of arrhythmogenic foci radiofrequency was applied under angiographic or ultrasonographic control. RESULTS: During 17 procedures, 40 pulmonary veins were mapped, 16 of which had local ectopic activity, related or not with the triggering of atrial fibrillation paroxysms. At the end of each procedure, suppression of arrhythmias was obtained in 8 patients, and elimination of pulmonary vein potentials was accomplished in 4. During the clinical follow-up of 9.6±3 months, 7 patients remained in sinus rhythm, 5 of whom were using antiarrhythmic drugs that had previously been ineffective. None of the patients had pulmonary hypertension or evidence of stenosis in the pulmonary veins. CONCLUSION: Selective and simultaneous catheterization of the 4 pulmonary veins with microcatheters for simultaneous recording of their electrical activity is a feasible and safe procedure that may help ablation of atrial fibrillation.

Biotechnological production and application of fructooligosaccharides

Currently, prebiotics are all carbohydrates of relatively short chain length. An important group is the fructooligosaccharides, which are a special kind of prebiotics associated to their selective stimulation of the activity of certain groups of colonic bacteria that have a positive and beneficial effect on intestinal microbiota, reducing incidence of gastrointestinal infections, respiratory and also possessing a recognized bifidogenic effect. Traditionally, these prebiotic compounds have been obtained through extraction processes from some plants, as well as through enzymatic hydrolysis of sucrose. However, different fermentative methods have also been proposed for the production of fructooligosaccharides, such as solid-state fermentation utilizing various agroindustrial by-products. By optimizing the culture parameters, fructooligosaccharides yields and productivity can be improved. The use of immobilized enzymes and cells has also been proposed as being an effective and economic method for large-scale production of fructooligosaccharides. This paper is an overview on the results of recent studies on fructooligosacharides biosynthesis, physicochemical properties, sources, biotechnological production and applications.

Investigações sobre doenças de Psittacideos

The present paper colligates the notions acquired in previous investigations, already published, and new observations upon diseases of the psittacidae, liable to be confused with psittacosis of parrots. The author calls attention to the indifference with regard to this question shown by investigators, even by those who dealt with the study of this disease on the occasion of the latest outbreak of psittacosis, in flagrant contrast with the researches upon the alterations induced by pathogenic agents of other diseases transmissible to man, when these agents pass through animals or when the latter are depositaries of the virus. This remark considerably enhances the importance of the presence paper from a hygienic and epidemiologic point of view, representing moreover a contribution to general knowledge and to veterinary medicine. The researches carried out since the appearance of the latest outbreak of psittacosis,-which occurred simultaneously with an epizooty in parrots lodged in aviary of the park of Agua Branca (Directory of Animal Industry of the State São Paulo)-led to the verification of the frequent existence in these animals of various diseases liable to be confused with psittacosis. These diseases are due to two kinds of pathogenic agents: virus and bacteria. In the first group there are to be found the diseases occasioned by the virus of human psittacosis, discovered by Western, Bedson and Simpson, and the disease me with in parrots coming from traders in S. Paulo. The infections by bacteria of the genus Salmonella and by those of other genera belong to the second group. As differential characters of the two infections due to virus, delineated on the strength of notions drawn from a detailed experimental study and from the literature on this subject, the following are given: ¹ Samples of our virus were sent, for comparison, to various investigators of psittacosis. Amongst them, Prof. M. Rivers acceded to our request; he found its nature to be different from that of the virus of psittacosis studiedby him. We are very much obliged to him for the attention he paid to this verification. Virus of psittacosis - Infectiousness: man, monkey, rabbit, mouse, hen, canary. Neurotropic affinity. Inclusions: small, protoplasmic. Exsiccation: the virus has good power of preservation. Symptoms: inactivity, drowsiness, frequent diarrhoea, oculo-nasal discharge and cough, coma. Duration: 4 to 5 days. Bodily lesions: congestion of intestines, splenomegaly. Virus of S. Paulo - Infects only psittacidae, particularly those of the genus Amazona. No localization in the nervous system. Large, nuclear. Is rapidly destroyed. Inactivity, inappetency, adynamia (drooping of the wings, indifference, leaning its beak against the bars of the cage in order not to fall down); profuse diarrhoea, of whitish stools, at times enterorrhagia; prolonged coma. 2 to 8 days. Foci of yellowish necrosis in liver, spleen and lung. At times, congestion of intestines. Characteristic features common to the two viruses.-They act in great dilutions, filter through tight candles though being partly retained, are preserved under glycerine or Bedson's solution, are stable at 55°C. heat and are destroyed by physical and chemical agents. Both virus diseases are very seldom met with in psittacidae: only once, amongst numberless sick parrots, the author met with a disease of the virus differring from that of psittacosis. This disease, greatly transmissible to man, ought to be more frequent, if it were common in parrots. On the contrary, bacteria cause diseases in these animals with great frequency, presenting variable characters, from a severe epizootic form, rapidly mortal, to ambulatory or silent forms, for the most part developing towards a cure or assuming a chronic character. Amongst the bacteria which cause the infection of this group the salmonellae predominate and amongst them the bacterium discovered by Nocard, as well as a species which in the course of this study is characterized under the name of Salmonella nocardi. The author believes that in the epizooty from which Nocard isolated his bacterium there was association of the virus-disease inducing the epizooty of that epoch in Paris with the bacterial disease, as must have happened in Argentina, where the disease was transmitted to man, and Santillan, according to Barros, isolated from the sick parrots bacteria of the genus Salmonella. The diseases of the two groups, that due to virus and that due to bacteria, are differentiated: Virus-diseases - Evolution: rapid, nearly always followed by death. Symptoms: sadness, profuse diarrhoea, of whitish stools, at times enterorrhagia, complete inappetency, adynamia, indifference, prolonged coma. Clinical forms: acute and subacute. Lesions: Foci of necrosis in liver and spleen without cellular reaction around the focus, yellow liver, multiple serositis. Presence of protoplasmic or nuclear granulations. Bacteriology: Complete lack or inconstant presence of bacteria in the organs and blood. Infectiousness of the organs and blood after filtration: positive. Bacterial diseases - Varies from one week to a month or more, not always fatal. Sadness, partial inappetency, tremblings, intensive thirst, mucous or mucosanguineous diarrhoea, lack of adynamia (reacts to stimulations and moves well at any time of the disease, though showing little disposition to locomotion), soiling of feathers. Frustrate, acute, subacute and chronic. Hepatic and intestinal cogestion, foci of necrosis in liver, spleen and lung with cellular reaction around the focus. Lack of granulations. Constant presence of bacteria in the organs and blood. Negative. The analysis of the litterature shows that the characteristic features of the diseases in parrots referred to parrot psittacosis, more frequently approach the bacterial diseases here described of these animals, a hypothesis which is reinforced by the observation of the greater frequency of infections...

Ascaridiose hepatica

The author describes a case of liver ascaridiasis in a girl, 1 year old, who also presented intestinal parasitism by 54 adult specimens pf Ascaris lumbricoides. The hepatic lesions consisted in several abscesses containing living adult worms along with dead specimens and in the formation of an inflammatory condition with pronounced production of fibrous connective tissue and lymphocytic infiltration. Special attention is attracted by the fact of the existence of numerous eggs of Ascaris lumbricoides in the innermost of the inflammatory tissue. The inflammatory foci met with are closely connected with the biliary ducts; the presence of eggs of Ascaris lumbricoides is found even within the epithelium. Apart from the zones affected by the process of ascaridiasis, the hepatic tissue is seen to be well preserved.

Atividades da estação biológica de Perús

The author who was appointed entomologist of the Biological Station in Perus, São Paulo, describes in this paper, the kind of work he has been doing there. He begins with a description of the organization of the Station and of the routine work as it was daily carried on there, by himself and his staff, during nearly 6 months. During the day as well as during the night, captures of jungle were made in the forest and the same was done by night, in the Station House chiefly when the athmosphere was damp, just before, during, or after a rain. There was also an intensive search for foci of mosquitoes' larves in the bromelias, in holes, in trees and in the soil. The larves found in these breeding places were brought to a larvarium established in the forest in a place close to the station where they were bred in holes of bambus which were very suitable for them. During daytime, only new hatched mosquitoes have been captured, but during the night it has been possible to catch, inside the Station house, many female mosquitoes, with developped eggs, so confirming Aragão's opinion, that mosquitoes biting during the day are always, newly hatched ones. Some species of Sabetini were captured only inside the Biological Station House, during the night. The habits of the following species were subjected to more accurate investigations. Aedes scapularis, Aedes leucocelaenus, Lutzia braziliae, Culex (Carolia) iridescens, Orthopodomyia albicosta, Goeldia palidiventer, Joblotia compressum, Wyeomyia longirostris, Sabetoides intermedius, Limatus durhami. The conditions of the temperature of the Station, did not permit the authour to obtain breedings of Aedes aegypti in the larvarium of the Station, even during he summer months. A great diminuitions of species of the jungle mosquitoes was observed, from January till June, that is, when temperature gets lower and lower. The author has made the interesting observation that some species of mosquitoes (Joblotia and Limatus), must take a meal of flowers or bee honey before they suck blood. A list of the mosquitoes captured during the months of February to June, in the Station is given.

Subsídio ao melhor conhecimento do tifo exantemático neotrópico no Brasil: presença do virus no leite

In articles, already published, we have proved that the strain V. B. of Brazilian virus, goes through the placenta (Macacus rhesus) (1) and the apparently normal gastro-intestinal tube (1934-1937) (Canis familiaris) (2). Today we present the idea that the Brazilian virus can reach the milk of an animal even when the latter has only the unapparent disease. In former articles (**), we have shown that the goat (Capra hircus) can be an excellent reservoir of Brazilian virus, having the strain V. B. in its blood and presenting a Weil Felix reaction high and in “group”, with the disease unapparent. When the goats are bred in the laboratory, and even in some foci of the disease, they give a negative Weil Felix, being zero for all the nine strains of Proteus. In the interior of Brazil, in many localities, goats substitute cows, in supplying milk for children and adults, and in some districts goat’s milk is considered superior to cow’s milk, possessing marvellous qualities for men, women an children. Having proved, now, that goat’s milk can contain the virus even when the animal presents nothing clinically, and having also shown that this virus goes through the digestive tube apparently sound, it is easy to understand how infants-in-arms, that is, only a few months old, living in strictly domestic surroundings, can contract the disease; we have many such cases on record. Protocol of the experiments: Goat nº 2, white, January 1948. This animal had been inoculated with the V. B. strain of the Brazilian virus in June 1947, via intra-peritoneal, presenting nothing then, not even a feverish reaction. On that occasion it was not possible to isolate the virus of the blood, although the Weil Felix reaction was positive, high and in “group”. Now January 17, 1948, seven months later, the same animal was reinoculated with a semple of virus V. B. in the same manner (intra-peritoneal) two days after bringing forth two sturdy kids. The virus V. B. was obtained from guinea-pig n. 7170 whose thermic graph was as follows: Temperatura – 38,8 – 39,1 – 39,5 – 39,4 –39,8 – 40,4 – 40,2 – 40,1 - + Necropsy – Typical lesions. The spleen weighed 5 grammes. With 3c.c. of emulsion from the nervous system of this guinea-pig, we inoculated not only the goat, as also two guineapigs, number 14 and number 5. The following is the thermic graph of one: - Guinea-pig n. 14 – 38,9 – 39,1 – 39,2 – 39.2 – 40,7 – 41,0 – 40,5 – 40,4 – 40,1 - + Typical lesions. Guinea-pig n. 2 presented the following thermic graph after the infective inoculation: - 39,5 – 39,7 – 39,7 – 39,7 – 39,5 – 39,3 – 39,5 – 39,5 – 39,5 – etc. Clinically, this animal presented nothing unusual, feeding well and suckling the kids normally. The Weil Felix reaction was positive, in “group” high very similar to the reaction obtained in June 1947, with the first infective inoculation. On the third, fourth, fifth, sixth and seventh day after the infective inoculation, we took milk from the goat and inoculated male guinea-pigs via intra-celular and via intra-peritoneal, giving 5 c.c. to each animal. Guinea-pig n. 4663, inoculated with 5 c.c. of milk, via intra-muscular, taken on the third day of the infectaive inoculation, presented the following thermic graph: - 38.8 (*) – 39,1 – 39,0 – 39,1 – 40,1 – 40,1 – 40,8 (**) – 40,8 – Killed – Typical deisions (***). The virus V. B. of this goat, circulated naturally in the blood up to the third day, having passed into the milk, producing nothing in the kids, on account of the natural resistance of these animals to the disease. The Weil Felix reaction and that of Widal for the Burcellas suis, abortus and militensis were negative for the goat and the kids. It is remarkable that, even with inoculation of the living virus after a period of seven months we cannot get a real and absolute immunity of sensitive animals. We shall return to this subject later. The hart Mazama simplicicornis may be a carrier of the virus in Brasil. The experimental serum against the virus of Exanthematic neotropical typhus has not protected guinea-pigs.

A doença de Chagas no Paraná

In recent speech in Curitiba (May 22nd, 1954), Dr. Mario Pinotti, Director, Serviço Nacional da Malaria, informed that his personnel started on February, 1953, a survey upon chagas Disease in 23 counties of the State of Paraná, South Brazil. out of 895 places surveyed, 678, or 75.7%, were infected by Triatoma infestans klug 1834 and in 234 out of those 678, or 34.5%, this vector was infected by Trypanosoma cruzi. The general natural infection of the insects examined reached 18.86%. The serological survey (Machado-Guerreiro test) was positive in 10.7% of the persons examined in jacarezinho and in 28.3% of those living in Bôa Vista. These data suggested the author to actualise the subject. During his control of severe outbreack of malaria in the North part of Paraná, from march to June 1917 he worked in 8 counties. March 1917 he photographed in Boa Vista four girls, severe cases of chronic malaria, two of which showed bi-palpebral oedema, later on considered by Dr. Pinho Simões (1943) as Romanã syndrome (created in 1935) and Prof. Salvador Mazza (1946) classified as typical cases of Chagas' Disease. now, being elapsed 36 years, the National Service of Malaria confirmed the discovery. The region surveyed was populated, in the beginning of this century, by immigrants from the State of Minas Gerais, from where the author believes that were imported the disease and its vectors. In April 1917 the A. discovered that the old town Jatahy was a big focus of Triatoma megista (now Panstrongylus megistus0. All its 43 houses were strongly infested by such hematophagus and amongst the 200 inhabitants seen many were suspicious cases of chronic cases of Chagas's Disease. In the Indians town (three tribes) of S. Pedro D' Alcantara, situated in front of Jatahy, in the left side of the river Tibagy, there were no Triatomas nor suspicious cases of trypanosomiasis. In 1919 the author started the control of the endemics by destroying the foci of Triatomas and reforming the housing. In 1946 he returned to jatahy and found the sanitary conditions of the town and its inhabitants much better. Climate of the region is favorable to spreading of all tropical diseases, being very suitable one for an extensive sanitary survey. In 1943 Dr. Pinho Simões examined 85 triatomas ( T. infestans) from six counties of the North region and found 40, or 46% infected by Trypanosoma cruzi. The highest incidences were; Joaquim Tavora 74.2% and Carlópolis 26.9%. These counties seem to be infested by Itaporanga county of São Paulo State. in 1953 Serviço nacional da Malária proved that 19 out of 23 counties surveyed were infested by Triatoma infestans. They examined 7,701 of this insect and found 1,453 positive for Trypanosoma cruzi, or 18.9%. in two counties, Jacarezinho and Sengés, were examined 2,588 human bloods, not selected, and 323, or 12.6% of such samples were positive for Chagas' Disease. This year the Malaria Service is doing insects survey in 25 other counties and DDTising infested domiciles of another eight. Such activity is very promising and should be extended to other places.

Terceira contribuicäo ao conhecimento do gênero Archytas Jaennicke, 1867: (Diptera, Tachinidae)

Twelve species of the genus Archytas Jennicke, 1867, eight of which described as new are studied and figured in detail. Definitions of the species are based mainly on characters of male genitalia. The male genital characters are the most significant for separation of the species and most demonstrative of their affinities. By examining a long series of species of this genus we came to the conclusion that the presence of one pair of median marginal bristles on the third abdominal tergite seems to be characteristic of the genus. This caracter apparently so important, is not however considered fundamental. The most significant example is found in Archytas lenkoi sp. n. and Archytas vexor Curran, 1928. In A. lenkoi we can find one or two pairs or thay may, less frquently, be absent. In A. vexor these bristles are lacking. The shape of the male copulatory apparatus of Jurinia nitidiventris Curran, 1928 refered to by CURRAN in his "Revision of Archytas", is not characteristic of any species of the group and so, is not considered in this paper. To help in the identification, the species studied here are divided into groups. The analis group" includes: A. apicifer (Walker, 1894), A. californiae (Walker, 1856), A. nivalis Curran, 1928, a. giacomellii (Blanchard, 1941), A. basifulvus (Walker, 1849), A. incasanus Townsend, 1912 and A. cirphis Curran, 1927. The identification of members of these group is extremely difficult owing both to their similarity in colour pattern and to their variability. They all have black testaceous or dark brown abdomen, the last segment pale or brownish pollinose; second segment without bristles; third with a pair of strong marginals, fourth and fifth with two rows of discals on apical third. The final determination often rests upon the structure of the male copulatory apparatus. Fortunately in this group, many of the forcipes superiores and palpi genitalium are strikingly different from one another. The "zikani group" includes: A. zikani sp. n., A seabrai sp. n., A. duckei sp. n. and A. vernalis Curran, 1928. This group may be characterized as follows: forcipes interiores absent; forcipes superiores strongly chitinized an dilated at anex. Within this group, the forcipes of. A. seabrai sp. n. do not present an aberrant form. The "dissimilis group" will be studied in forthcoming papers. The limits of the genus Archyta Jaen. are not as yet sharply difined, the evaluation of the significance of each character used in the definition remaining as most difficult problem. The distinction between Archytas and other related genera is very difficult, chiefly because it is based on variable characters. In this paper we place the genera Parafabricia Towsend, 1931, Itachytas Blanchard, 1940, Archynemochaeta Blanchard, 1941, Proarchytoides Blanchard, 1941 and Archytodejeania Blanchard, 1941 in the synonymy of Archytas Jaen. The detailed examination of the characters used in their definition, proved them to be fundamentally proposed on basis of chaetotasy, these characters alone being precarious, because of the considerabel intraspecifical variation. The type of the new species are in the Oswaldo Cruz Institute collection. Rio de Janeiro, Brazil, and paratypes in the collections of the followings institutions: Departamento de Zoologia da Secretaria de Agricultura do Estado de São Paulo; Instituto de Ecologia e Experimemtação Agrícolas; Departamento de Defesa Sanitária Vegetal; Campos Seabra collection; and Barbiellini collection.

Immunopathology of Schistosoma mansoni infection in rabbits: (A preliminary report)

Five rabbits infected with Schistosoma mansoni showed marked resistance, which resulted in low worm recovery and low egg production. Pathological changes appeared in liver and intestines as scattered foci of eosinophilic infiltration around immature eggs, with only occasional granulomatous formation. Antibodies to ovular and adult worm structures were demonstrated by immunofluorescence in the sera of rabbits prior to infection (natural antibodies) and specially following infection by S. mansoni. These findings point out to the peculiarities of the immunopathology of schistosomiasis in rabbits.

Study of an outbreak of cutaneous leishmaniasis in Venezuela: the role of domestic animals

During an outbreak of cutaneous leishmaniasis in a locality (Las Rosas, Cojedes State, venezuela) previously non-endemic, 12.9% of humans, 7% of dogs and 21.4% of donkeys (Equus asinus) had lesions with paraites. The agent in the three hosts was identified as Leishmania braziliensis, subspecies braziliensis at least in man and donkey. The probable vector was Lutzomyia panamensis. No infection was found in a small sample of wild mammals examined. The outbreak was apparently linked with the importation of donkeys with ulcers, from endemic areas. The Authors call attention to the fact that not only in the foci of "uta", but also in areas of the other forms of American cutaneous leishmaniasis, dogs are frequently found infected. They emphasize the necessity of searching for the infection in donkeys and of performing hemocultures and xenodiagnosis with sandflies in human, canine and equine cases, to verify their possible role as sources of infection, and not merely as dead ends in the epidemiological chain of the disease.

T Cells Bearing a Chimeric Antigen Receptor against Prostate-Specific Membrane Antigen Mediate Vascular Disruption and Result in Tumor Regression.

Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of protumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here, we describe the ability of chimeric antigen receptor (CAR)-bearing T cells to recognize human prostate-specific membrane antigen (hPSMA) on endothelial targets in vitro as well as in vivo. CAR T cells were generated using the anti-PSMA scFv, J591, and the intracellular signaling domains: CD3ζ, CD28, and/or CD137/4-1BB. We found that all anti-hPSMA CAR T cells recognized and eliminated PSMA(+) endothelial targets in vitro, regardless of the signaling domain. T cells bearing the third-generation anti-hPSMA CAR, P28BBζ, were able to recognize and kill primary human endothelial cells isolated from gynecologic cancers. In addition, the P28BBζ CAR T cells mediated regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine models of ovarian cancers populated by murine vessels expressing hPSMA, the P28BBζ CAR T cells were able to ablate PSMA(+) vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide a strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA. Cancer Immunol Res; 3(1); 68-84. ©2014 AACR.

Comprehensive Expression Analyses of Neural Cell-Type-Specific miRNAs Identify New Determinants of the Specification and Maintenance of Neuronal Phenotypes.

MicroRNAs (miRNAs) have been shown to play important roles in both brain development and the regulation of adult neural cell functions. However, a systematic analysis of brain miRNA functions has been hindered by a lack of comprehensive information regarding the distribution of miRNAs in neuronal versus glial cells. To address this issue, we performed microarray analyses of miRNA expression in the four principal cell types of the CNS (neurons, astrocytes, oligodendrocytes, and microglia) using primary cultures from postnatal d 1 rat cortex. These analyses revealed that neural miRNA expression is highly cell-type specific, with 116 of the 351 miRNAs examined being differentially expressed fivefold or more across the four cell types. We also demonstrate that individual neuron-enriched or neuron-diminished RNAs had a significant impact on the specification of neuronal phenotype: overexpression of the neuron-enriched miRNAs miR-376a and miR-434 increased the differentiation of neural stem cells into neurons, whereas the opposite effect was observed for the glia-enriched miRNAs miR-223, miR-146a, miR-19, and miR-32. In addition, glia-enriched miRNAs were shown to inhibit aberrant glial expression of neuronal proteins and phenotypes, as exemplified by miR-146a, which inhibited neuroligin 1-dependent synaptogenesis. This study identifies new nervous system functions of specific miRNAs, reveals the global extent to which the brain may use differential miRNA expression to regulate neural cell-type-specific phenotypes, and provides an important data resource that defines the compartmentalization of brain miRNAs across different cell types.

Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene.

Eukaryotic cells generate energy in the form of ATP, through a network of mitochondrial complexes and electron carriers known as the oxidative phosphorylation system. In mammals, mitochondrial complex I (CI) is the largest component of this system, comprising 45 different subunits encoded by mitochondrial and nuclear DNA. Humans diagnosed with mutations in the gene NDUFS4, encoding a nuclear DNA-encoded subunit of CI (NADH dehydrogenase ubiquinone Fe-S protein 4), typically suffer from Leigh syndrome, a neurodegenerative disease with onset in infancy or early childhood. Mitochondria from NDUFS4 patients usually lack detectable NDUFS4 protein and show a CI stability/assembly defect. Here, we describe a recessive mouse phenotype caused by the insertion of a transposable element into Ndufs4, identified by a novel combined linkage and expression analysis. Designated Ndufs4(fky), the mutation leads to aberrant transcript splicing and absence of NDUFS4 protein in all tissues tested of homozygous mice. Physical and behavioral symptoms displayed by Ndufs4(fky/fky) mice include temporary fur loss, growth retardation, unsteady gait, and abnormal body posture when suspended by the tail. Analysis of CI in Ndufs4(fky/fky) mice using blue native PAGE revealed the presence of a faster migrating crippled complex. This crippled CI was shown to lack subunits of the "N assembly module", which contains the NADH binding site, but contained two assembly factors not present in intact CI. Metabolomic analysis of the blood by tandem mass spectrometry showed increased hydroxyacylcarnitine species, implying that the CI defect leads to an imbalanced NADH/NAD(+) ratio that inhibits mitochondrial fatty acid β-oxidation.

Carcinoembryonic antigen (CEA) in non digestive cancerous and normal tissues.

Carcinoembryonic antigen (CEA), immunologically identical to CEA derived from colonic carcinoma, was identified and purified from perchloric acid (PCA) extracts of bronchial and mammary carcinoma. CEA extracted from bronchial and mammary carcinoma was quantitated by single radial immunodiffusion and was found to be in average about 50-75 times less abundant in these tumors than in colonic carcinoma. CEA could also be detected in one normal breast in lactation and at lower concentrations in normal lung (1000-4000 times lower than in colonic carcinoma). The small amounts of CEA present in normal tissues are distinct from the glycoprotein of small mol. wt showing only partial identity with CEA, that we recently identified and extracted in much larger quantities from normal lung and spleen. The demonstration of the presence of CEA in non digestive carcinoma by classical gel precipitation analysis suggests that the CEA detected in the plasma of such patients by radioimmunoassay is also identical to colonic carcinoma CEA. Our comparative study of plasma CEA from bronchial and colonic carcinoma, showing that CEA from both types of patient has the same elution pattern on Sephadex G-200 and gives parallel inhibition curves in the radioimmunoassay, is in favor of this hypothesis. However, it should not be concluded that all positive CEA radioimmunoassay indicate the presence of an antigen identical to colonic carcinoma CEA. A word of warning concerning the interpretation of radioimmunoassay is required by the observation that the addition of mg amounts of PCA extract of normal plasma, cleared of CEA by Sephadex filtration, could interfere in the test and mimic the presence of CEA.

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of myotonic dystrophy.

Acute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1). Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs) and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding mechanisms of respiratory deficiency should guide pharmaceutical and clinical research towards better therapy for the respiratory deficits associated with DM1.