Clarifying the role of neuroticism in suicidal ideation and suicide attempt among women with major depressive disorder.

BACKGROUND: Prior research consistently demonstrates that neuroticism increases risk for suicidal ideation, but the association between neuroticism and suicidal behavior has been inconsistent. Whereas neuroticism is recommended as an endophenotype for suicidality, the association of neuroticism with attempted suicide warrants clarification. In particular, prior research has not distinguished between correlates of attempted suicide, correlates of suicidal ideation, and correlates of comorbid psychopathology. METHODS: The present study used the CONVERGE study, a sample of 5864 women with major depressive disorder (MD) and 5783 women without MD throughout China. Diagnoses, suicidal ideation, and attempted suicide were assessed with the Composite International Diagnostic Interview (CIDI). Neuroticism was assessed with the neuroticism portion of the Eysenck Personality Questionnaire. RESULTS: Results replicate prior findings on the correlates of suicidal ideation, particularly elevated neuroticism among individuals who report prior suicidal ideation. Moreover, as compared with individuals who reported having experienced only suicidal ideation, neuroticism was associated with decreased likelihood of having attempted suicide. CONCLUSIONS: The association of neuroticism with suicidality is more complicated than has been previously described. Whereas neuroticism increases risk for suicidal ideation, neuroticism may decrease risk for a suicide attempt among individuals with suicidal ideation. These results have implications for the assessment of risk for a suicide attempt among individuals who report suicidal ideation and addresses prior discordant findings by clarifying the association between neuroticism and attempted suicide.

Peripheral blood gene expression signature differentiates children with autism from unaffected siblings.

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders with high heritability, yet a majority of genetic contribution to pathophysiology is not known. Siblings of individuals with ASD are at increased risk for ASD and autistic traits, but the genetic contribution for simplex families is estimated to be less when compared to multiplex families. To explore the genomic (dis-) similarity between proband and unaffected sibling in simplex families, we used genome-wide gene expression profiles of blood from 20 proband-unaffected sibling pairs and 18 unrelated control individuals. The global gene expression profiles of unaffected siblings were more similar to those from probands as they shared genetic and environmental background. A total of 189 genes were significantly differentially expressed between proband-sib pairs (nominal p < 0.01) after controlling for age, sex, and family effects. Probands and siblings were distinguished into two groups by cluster analysis with these genes. Overall, unaffected siblings were equally distant from the centroid of probands and from that of unrelated controls with the differentially expressed genes. Interestingly, five of 20 siblings had gene expression profiles that were more similar to unrelated controls than to their matched probands. In summary, we found a set of genes that distinguished probands from the unaffected siblings, and a subgroup of unaffected siblings who were more similar to probands. The pathways that characterized probands compared to siblings using peripheral blood gene expression profiles were the up-regulation of ribosomal, spliceosomal, and mitochondrial pathways, and the down-regulation of neuroreceptor-ligand, immune response and calcium signaling pathways. Further integrative study with structural genetic variations such as de novo mutations, rare variants, and copy number variations would clarify whether these transcriptomic changes are structural or environmental in origin.

Synthesis of stress proteins in rat cardiac myocytes 2-4 days after imposition of hemodynamic overload.

Isolated adult myocytes incubated with [35S]methionine were used to study the expression of proteins in the rat heart during the first 2 wk after either pressure or volume overload. In both models an early (2-4 d) and transient expression of three major stress proteins (heat shock protein [HSP] HSP 70, HSP 68, and HSP 58) was observed together with an increased synthesis of putative ribosomal proteins. Only traces of 35S-labeled HSPs were detected in controls and sham-operated animals. The three stress proteins were identified by their migration in two-dimensional gels, by comigration with HSPs, which had been induced in myocytes by incubation at 41 degrees C and immunoblot analysis using antisera directed against the 70-kD protein. Immunohistochemical staining of HSP 70 in rod-shaped myocytes and detection by immunoblot showed that HSP 70 was equally present and distributed in both sham-operated and overloaded hearts, and provided no evidence for a subpopulation of myocytes acutely involved in the increased expression of HSP 70. It is suggested that the transient expression of HSPs that occurs during the early adaptation of the myocardial cells to overload could confer some degree of protection to the actively growing myocytes.

Accumulation of fetal fibronectin mRNAs during the development of rat cardiac hypertrophy induced by pressure overload.

Cardiac pressure overload induces a shift towards the fetal form of major proteins expressed by the myocytes, and an accumulation of extracellular matrix proteins. One of them, fibronectin (FN), accumulates soon after the imposition of pressure overload. Because FN exists both as cellular FN (c-FN) locally synthesized by nonmuscle cells and as "plasma-FN" (p-FN) synthesized by the hepatocytes, the first issue of this study was to determine whether FN accumulation within the myocardium in response to pressure overload is paralleled by a local increase in mRNA. The expression of c-FN isoforms being developmentally regulated in a tissue-specific manner, the types of FN exons expressed by cardiac cells were analyzed. Pressure overload was induced in 25-d-old rats by stenosis of the thoracic aorta. Using in situ hybridization, we show that the mRNAs encoding the fetal forms of c-FN are accumulated in the interstitial tissue of fetal rat hearts but are absent in adult. 1-3 d after aortic stenosis, the fetal forms of c-FN mRNAs were found in the wall of coronary arteries and in focal areas of the myocardium. Thus nonmuscle cells and smooth muscle cells, like myocytes, do respond to pressure overload by reexpressing fetal gene transcripts.

Self-protection by cardiac myocytes against hypoxia and hyperoxia.

Cardiac muscle must maintain a continuous balance between its energy supply and work performed. An important mechanism involved in achievement of this balance is cross talk via chemical signals between cardiac myocytes and the cardiac muscle vascular system. This has been demonstrated by incubating isolated cardiac myocytes in different concentrations of oxygen and then assaying the conditioned media for vasoactive substances on isolated aortic rings and small-resistance arteries. With increasing oxygen concentrations above 6%, cardiac myocytes produce increasing amounts of angiotensin I, which is converted to angiotensin II by the blood vessel. The angiotensin II stimulates vascular endothelial cells to secrete endothelin and increase vascular tone. Below 6% oxygen, cardiac myocytes secrete adenosine, which acts directly on vascular smooth muscle to block the effect of alpha-adrenergic agonists and reduce vascular tone. In an intact heart, the net effect of these 2 regulatory systems would be the maintenance of oxygen concentration within a narrow range at the cardiac myocytes. By acting as oxygen sensors, cardiac myocytes modulate vascular tone according to the needs of the myocytes and reduce potential problems of hypoxia and extensive formation of reactive oxygen species.

Study of regulation of mitochondrial respiration in vivo. An analysis of influence of ADP diffusion and possible role of cytoskeleton.

The purpose of this work was to investigate the mechanism of regulation of mitochondrial respiration in vivo in different muscles of normal rat and mice, and in transgenic mice deficient in desmin. Skinned fiber technique was used to study the mitochondrial respiration in the cells in vivo in the heart, soleus and white gastrocnemius skeletal muscles of these animals. Also, cardiomyocytes were isolated from the normal rat heart, permeabilized by saponin and the "ghost" (phantom) cardiomyocytes were produced by extraction of myosin with 800 mM KCl. Use of confocal immunofluorescent microscopy and anti-desmin antibodies showed good preservation of mitochondria and cytoskeletal system in these phantom cells. Kinetics of respiration regulation by ADP was also studied in these cells in detail before and after binding of anti-desmine antibodies with intermediate filaments. In skinned cardiac or soleus skeletal muscle fibers but not in fibers from fast twitch skeletal muscle the kinetics of mitochondrial respiration regulation by ADP was characterized by very high apparent Km (low affinity) equal to 300-400 microM, exceeding that for isolated mitochondria by factor of 25. In skinned fibers from m. soleus, partial inhibition of respiration by NaN3 did not decrease the apparent Km for ADP significantly, this excluding the possible explanation of low apparent affinity of mitochondria to ADP in these cells by its rapid consumption due to high oxidative activity and by intracellular diffusion problems. However, short treatment of fibers with trypsin decreased this constant value to 40-70 microM, confirming the earlier proposition that mitochondrial sensitivity to ADP in vivo is controlled by some cytoplasmic protein. Phantom cardiomyocytes which contain mostly mitochondria and cytoskeleton and retain the normal shape, showed also high apparent Km values for ADP. Therefore, they are probably the most suitable system for studies of cellular factors which control mitochondrial function in the cells in vivo. In these phantom cells anti-desmin antibodies did not change the kinetics of respiration regulation by ADP. However, in skinned fibers from the heart and m. soleus of transgenic desmin-deficient mice some changes in kinetics of respiration regulation by ADP were observed: in these fibers two populations of mitochondria were observed, one with usually high apparent Km for ADP and the second one with very low apparent Km for ADP. Morphological observations by electron microscopy confirmed the existence of two distinct cellular populations in the muscle cells of desmin-deficient mice. The results conform to the conclusion that the reason for observed high apparent Km for ADP in regulation of oxidative phosphorylation in heart and slow twitch skeletal muscle cells in vivo is low permeability of mitochondrial outer membrane porins but not diffusion problems of ADP into and inside the cells. Most probably, in these cells there is a protein associated with cytoskeleton, which controls the permeability of the outer mitochondrial porin pores (VDAC) for ADP. Desmin itself does not display this type of control of mitochondrial porin pores, but its absence results in appearance of cells with disorganised structure and of altered mitochondrial population probably lacking this unknown VDAC controlling protein. Thus, there may be functional connection between mitochondria, cellular structural organisation and cytoskeleton in the cells in vivo due to the existence of still unidentified protein factor(s).

Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass.

BACKGROUND: It is not known whether developmental and neurological outcomes in the preschool period differ depending on whether the predominant vital organ support strategy used in infant heart surgery was total circulatory arrest (CA) or low-flow cardiopulmonary bypass. METHODS AND RESULTS: Infants with D-transposition of the great arteries who underwent an arterial-switch operation were randomly assigned to a support method consisting predominantly of CA or low-flow cardiopulmonary bypass. Developmental and neurological status were evaluated blindly at 4 years of age in 158 of 163 eligible children (97%). Neither IQ scores nor overall neurological status were significantly associated with either treatment group or duration of CA. The CA group scored lower on tests of motor function (gross motor, P=0.01; fine motor, P=0.03) and had more severe speech abnormalities (oromotor apraxia, P=0.007). Seizures in the perioperative period, detected either clinically or by continuous electroencephalographic monitoring, were associated with lower mean IQ scores (12.6 and 7.7 points, respectively) and increased risk of neurological abnormalities (odds ratios, 8.4 and 5.6, respectively). The performance of the full cohort was below expectations in several domains, including IQ, expressive language, visual-motor integration, motor function, and oromotor control. CONCLUSIONS: Use of CA to support vital organs during open heart surgery in infancy is associated, at the age of 4 years, with worse motor coordination and planning but not with lower IQ or with worse overall neurological status.

General health status of children with D-transposition of the great arteries after the arterial switch operation.

BACKGROUND: To study the long-term impact on general health status of D-transposition of the great arteries (D-TGA) after the arterial switch operation (ASO) during infancy, we asked parents to complete the Child Health Questionnaire, Parent Form-50 when their children were 8 years old. METHODS AND RESULTS: Of 160 eligible patients, questionnaires were completed for 155 subjects (96%). Median age at surgery was 6 days (range 1 to 67 days), and median age at completion of the Child Health Questionnaire was 8.1 years (7.6 to 10.0 years). Subsequent to questionnaire completion, children underwent psychometric testing. Mean Physical Health Summary and Psychosocial Summary scores were 54.0+/-6.1 and 49.7+/-9.9, respectively, which were similar to those of normal subjects. Compared with the normative sample, parents of D-TGA patients reported more problems with attention, learning, and speech, as well as greater frequency of developmental delay (P<0.001 for each). Worse Psychosocial Summary scores were significantly associated with lower full-scale IQ (P=0.001) and lower achievement in reading (P=0.005) and math (P=0.007). Worse Physical Health Summary scores were associated with longer hospital stay after the ASO (P=0.02). General health status scores were not significantly related to presence of ventricular septal defect, age at surgery, perfusion variables during the ASO, sex, or history of cardiac reoperation. CONCLUSIONS: At age 8 years, children with D-TGA after ASO have an overall physical and psychosocial health status similar to that of the general population. Lower IQ and academic achievement are associated with worse psychosocial health status, whereas longer hospital course after initial surgery is associated with worse physical health status.

Expression of fibronectin during rat fetal and postnatal development: an in situ hybridisation and immunohistochemical study.

OBJECTIVE: Fibronectin is a protein of the extracellular matrix with numerous binding sites to the other elements of the matrix and to the cells. The aim of this study was to determine the relative importance of fibronectin isoform expression (FN-EIIIA, FN-EIIIB) during fetal and postnatal development of the rat heart. METHODS: In situ hybridisation and immunolabelling approaches were used to describe the cellular synthesis of fibronectin and its distribution throughout the rat heart from 11 d postconception until adulthood. The distribution of fibronectin was compared to that of laminin and of alpha type III procollagen. RESULTS: The accumulation and pattern of distribution of the major fibronectin mRNA isoforms were identical, that is, there was a progressive decrease in their accumulation as a function of time after 11 d postconception, resulting in a complete absence in the adult. The distribution of fibronectin and procollagen type III mRNAs were, however, quite distinct. At the protein level the time course of synthesis and secretion of the locally synthesised fibronectin (c-FN) did not follow fibronectin mRNA expression, the accumulation of the protein being rather poor, except just before birth, where it was found mainly in the coronary vessels. CONCLUSIONS: During the development of the fetal rat heart fibronectin gene transcription is active and progressively decreases with age, whereas the translation of the mRNAs into their corresponding proteins is always relatively poor. If fibronectin is involved in fetal and postnatal morphogenesis of the rat myocardium, it is the plasma form (p-FN) that is most probably involved in the process of growth and differentiation of the rat heart.

Diuretic effects on cardiac hypertrophy in the stroke prone spontaneously hypertensive rat.

OBJECTIVE: The aim was to compare the effects of two diuretics, indapamide and hydrochlorothiazide, on cardiac hypertrophy in stroke prone spontaneously hypertensive rats (SHR-SP). METHODS: Six week old SHR-SP, on a 1% sodium chloride water intake, were treated with oral indapamide (3 mg.kg-1 x d-1) or hydrochlorothiazide (20 mg.kg-1 x d-1) over a 44 d period. The hypertrophic process was evaluated by classical indices and by the morphological analysis of myocyte cross sectional area, coronary artery thickness, and immunohistochemical analysis of interstitial fibrosis. RESULTS: In the untreated SHR-SP on 1% sodium chloride, all animals developed severe hypertension and cardiac hypertrophy when compared to normotensive salt loaded WKY by 13 weeks of age. In salt loaded SHR-SP treated with indapamide or hydrochlorothiazide, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP, at 259(7) and 245(7) mm Hg respectively, v 300(11) mm Hg, p < or = 0.05. Myocyte enlargement appears to be the main feature involved in the development of cardiac hypertrophy in the SHR-SP. By the end of treatment both indapamide and hydrochlorothiazide prevented the development of cardiac hypertrophy evaluated by heart weight to body weight ratio [4.69(0.07) and 4.61(0.08) respectively, v 5.39(0.13), p < or = 0.001] and myocyte hypertrophy (-33% and -21% of the SHR-SP values, p < or = 0.001). Myocardial interstitial fibrosis and perivascular fibrosis were practically absent in the two treated groups. CONCLUSIONS: Our results allow the characterisation of SHR-SP cardiac hypertrophy and indicate that the two types of chronic diuretic treatment prevent SHR-SP cardiac hypertrophy with a drug specific efficiency.

Expression of laminin alpha2 chain during normal and pathological growth of myocardium in rat and human.

OBJECTIVES: Fibrosis is a classical feature of cardiac hypertrophy. To date changes within the basal lamina during normal and pathological cardiac growth have been poorly investigated. The goal of the present study was to determine if the expression of the muscle specific subunit of merosin (laminin alpha2 chain) together with that of fibronectin (FN) is modified in the diseased human heart. Laminin alpha2 chain expression was also investigated during physiological and pathological cardiac growth in the rat. METHODS: In ten normal human hearts and ten hearts with idiopathic dilated cardiomyopathy (IDCM), the laminin-alpha2 and FN mRNA levels were quantified by slot-blot using total RNA and the protein distribution was analysed using an immunofluorescence approach. In Wistar rats, laminin alpha2 and FN mRNA expression was analyzed using RNase protection assay (RPA) and slot-blot assays. RESULTS: The amount of laminin alpha2 mRNA did not vary in normal and pathological human hearts whereas it was significantly decreased in renovascular hypertensive rats (-20%) P<0.05 versus normal tissue). The amount of fibronectin mRNA increased in IDMC patients (x2, P<0.05 versus normal tissue), but was unchanged in hypertensive rats. A negative correlation was found between the cardiac laminin-alpha2 level and the age of the patients whatever the cardiac status. During postnatal development in the rat, a similar decrease in cardiac laminin-alpha2 level was observed between 3 and 30 weeks of age. Finally, the immunofluorescent approach failed to detect any alteration in laminin alpha2 distribution within the human myocardium. CONCLUSION: These data indicate that an imbalance between myocyte hypertrophy and the level of laminin-alpha2 might contribute to alterations in sarcolemmal properties, which occur during the development of cardiac hypertrophy and its transition to cardiac failure.

Different distributions of microtubules, desmin filaments and isomyosins during the onset of cardiac hypertrophy in the rat.

To elucidate the role of the cytoskeleton in the development of adult heart, microtubules and intermediate filaments of desmin were studied in young and adult rat heart myocytes during the onset of growth, after mechanical overloading induced by aortic stenosis. Such overloading is known to cause heart hypertrophy by stimulating overall protein synthesis, and to initiate a shift in myosin isozymes. For this study, we used double immunolabelling of isolated myocytes with specific antibodies raised against tubulin, desmin, and the two main isomyosins V1 and V3. Whereas desmin remained unchanged, tubulin was redistributed in arrays parallel to the long axis of the myocytes, and was densest around the nuclei. Alterations in the microtubule pattern were observed very early after aortic stenosis, during the onset of heart growth; they were transitory, and did not occur simultaneously in all myocytes. Chronological examination of myocytes labelling with both antitubulin and anti V3 myosin clearly suggested that the transitory alteration in the microtubule pattern was an early event preceding the change in the expression of the myosin gene. Results, observed in young rats, in which mitosis is stimulated by overloading, and in adult rats, exhibiting no mitosis, showed that microtubules are involved in the development of cells in which mitosis does not occur. This work provides the first evidence of a correlation in functional adult heart, between the reorganization of cytoplasmic microtubules and the onset of growth.

Immunological quantitation and localization of tubulin in adult rat heart isolated myocytes.

Isolated myocytes were purified from adult rat heart. Identification and localization of microtubules and quantitation of tubulin in these cells were performed by immunochemical procedures. Antibodies were raised against brain tubulin and purified by affinity chromatography. An enzyme-linked immunosorbent assay, ELISA, was developed for quantitation of tubulin. It allowed the measurement of 10 to 500 ng of tubulin. Tubulin content in adult rat cardiac myocytes was found to be approximately 10 micrograms per 100 mg of the total protein content. By means of a double immunofluorescence technique, the microtubule network, identified with antitubulin, was studied in reference to the sarcomeric A band labeled with antibodies specific to myosin heavy chains. The basis for identifying the microtubule network have included the use of specific antitubulin immunoglobulins and the sensitivity of the specific labeling of the network to antimitotic drugs and low temperature. It was found that microtubules were organized mainly around the nuclei, with important concentrations at the poles, showing extensions in the cone and in the cytoplasm as loosely organized loops. The shape of adult cardiac myocyte was not dependent upon the integrity of the microtubule network.

Characterization of a cytosolic triiodothyronine binding protein in atrium and ventricle of rat heart with different sensitivity toward thyroid hormone levels.

Cytosolic T3-binding protein (CTBP) has been identified in both the ventricle and atrium of adult rat hearts. Its biochemical characteristics and concentration have been determined in the two tissues as a function of thyroid hormone level. In both tissues association and dissociation constants were, respectively, k+1 = 1.3 x 10(8) M-1/min and k-1 = 0.025 min-1. Scatchard analysis of T3 equilibrium binding data revealed a single class of binding sites (Ka = 3.8 x 10(8) M-1). The maximal binding capacity (MBC) was 1400 fmol/mg protein in the ventricle and 730 fmol/mg protein in the atrium. The apparent mol wt of CTBP, determined by gel filtration, was 63.000. Among the thyroid hormone analogs tested in ventricular cytosol, D-T3 had the highest affinity, followed by L-T3, L-T4, 3,3',5-triiodothyroacetic acid, and rT3. These characteristics were very similar to those previously described for rat brain, and dog and rat liver and kidney CTBP. In hypothyroid rats MBC was only increased in the atrium (50-100%); after a single injection of T4 (2 micrograms/10 g BW 3 or 18 h before death) values returned to normal in the atrium and declined in the ventricle (-35%). During postnatal development, the highest MBC value (2000 fmol T3/mg protein) was observed in atria on day 10, i.e. when the serum T4 level was still low, and in the ventricle on day 30 (4000 fmol T3/mg protein) when the serum T4 level was at its highest. Binding affinities were similar in the two tissues at all ages studied. It was twice as high in both these tissues during the first week of development than in adulthood. These results favor a thyroid hormone down-regulation of the binding capacity of CTBP that would be more sensitive to the hormone in the atrium than in the ventricle.

Microvasculature in angiotensin II-dependent cardiac hypertrophy in the rat.

The long-lasting effect of angiotensin II (Ang II) on the microvasculature in the rat left ventricle was studied. Immunolabeling of ventricular cryosections combined with morphometric analysis allowed us to (1) distinguish between capillaries and arterioles and (2) precisely evaluate their respective densities in the endomyocardium. Ang II-induced hypertensive cardiac hypertrophy was associated with an 18% decrease in capillary density (P<0.05) and an increase in arteriole density (+54%, P<0.001). Treatments with losartan or PD123319, the respective antagonists of the angiotensin subtype 1 and subtype 2 receptors, prevented the increase in arteriolar density, whereas only losartan, which restored normal arterial pressure, prevented changes in capillary density. Taken together, these results indicate that Ang II-induced cardiac hypertrophy was associated with capillary rarefaction and arteriolar growth, the 2 processes being independently regulated.

Arterial smooth muscle cell phenotype in stroke-prone spontaneously hypertensive rats.

The aim of this study was to determine the phenotype of smooth muscle cells in the arteries of chronically hypertensive animals and to analyze the effects of treatments known to increase the survival of the animal without a clear effect on its hypertensive state. Stroke-prone spontaneously hypertensive rats (SHRSP) kept on a 1% sodium drinking solution were untreated or treated with one of two diuretics, indapamide (3 mg/kg per day) or hydrochlorothiazide (20 mg/kg per day), from 6 to 13 weeks of age. Phenotype was characterized by the immunolabeling of arteries with antibodies raised against a cellular form (EIIIA) of fibronectin, alpha-smooth muscle actin, and nonmuscle myosin. We demonstrated that phenotypes of smooth muscle cells of the SHRSP differ from those found in Wistar-Kyoto rats. The difference in phenotype is specific for the vessel type: ie, an increased expression of nonmuscle myosin in the aorta and of both EIIIA fibronectin and nonmuscle myosin in the coronary arteries. The two diuretics (1) had no effect on blood pressure, (2) prevented or did not prevent the increase in medial thickness, and (3) prevented changes in both smooth muscle cell phenotype and ischemic tissular lesions. Taken together, the results suggest that in SHRSP the changes in the phenotype of smooth muscle cells and the thickness of arteries are unrelated events. We propose that the maintenance of the contractile phenotype of the arterial smooth muscle cells could be an essential parameter involved in the prevention of the deleterious consequences characteristic of a severe hypertensive state.

The sarco(endo)plasmic reticulum Ca(2+)-ATPase mRNA isoform, SERCA 3, is expressed in endothelial and epithelial cells in various organs.

The sarco(endo)plasmic reticulum Ca(2+)-ATPase mRNA isoform, SERCA 3, was previously shown to be expressed in a great variety of muscle and non-muscle tissues [(1989) J. Biol. Chem. 264, 18568] but its cellular localization within these organs was unknown. We have used in situ hybridization and RNase protection techniques to demonstrate that SERCA 3 mRNA is expressed in specific cell types, namely the endothelial and epithelial cells.

Storage of phosphorylated desmin in a familial myopathy.

The quantity and the electrophoretic characteristics of desmin were analyzed in a familial skeletal muscle disorder, characterized by the intra-sarcoplasmic accumulation of an electron-dense granulo-filamentous material facing the Z-lines and reacting strongly with polyclonal anti-desmin antibodies. The analysis was performed on biopsies from the deltoid muscles of 4 patients, members of 2 families. In the 4 biopsies, an increase in the relative amount of desmin compared to that of actin or insoluble proteins (3 fold) and in the number of isovariants (6 instead of 3) was observed. The isovariants of desmin were similar to those described in Purkinje fibres of the heart as a phosphorylated form of the protein [(1987) Eur. J. Cell Biol. 44, 68-78]. Therefore, post-translational events could affect both the polymerization and the amount of desmin filaments in this autosomal dominant familial myopathy.

Mechanogenetic regulation of transcription.

In many biological systems mechanical forces regulate gene expression: in bacteria changes in turgor pressure cause a deformation of the membrane and induce the expression of osmoregulatory genes; in plants gravity regulates cell growth ('geotropism'); in mammals stretching a muscle induces hypertrophy which is accompanied by qualitative changes in protein synthesis. Consequently, the term 'mechanogenetic control' seems to be a suitable common name for all these processes. The mechanism by which mechanical factors modulate transcriptional activity is still unknown. The purpose of this review is to bring together data from different fields in order to obtain a better understanding of the mechanogenetic control of cell growth.

Phenylephrine, vasopressin and angiotensin II as determinants of proto-oncogene and heat-shock protein gene expression in adult rat heart and aorta.

The expression of two oncogenes (conc) c-myc and c-fos, coding for nuclear proteins which play a regulatory role in growth and differentiation, and of two genes coding for two heat shock proteins (HSP) 68 (molecular weight 68,000) and 70 (molecular weight 70,000), which have a protective function during stress, have been investigated by Northern blot analysis of the total RNA, extracted from adult rat ventricle and aorta. (1) The two onc transcripts are absent from these tissues but their expression can be enhanced by a pretreatment with cycloheximide. (2) The HSP70 is, in part, constitutive, while HSP68 is not; both are thermo-inducible in an isolated coronary perfused rat heart. (3) The four messenger RNA (mRNA) are expressed in both ventricles and aorta, 1 or 2 hours after i.p. injection of 6 mg/kg phenylephrine or 12 IU/kg of vasopressin. (4) They are also induced by a continuous or discontinuous injection of angiotensin II (7.5 micrograms/kg per min) for 1-2 h, but only in the aorta. The lack of ventricular response to angiotensin II in rat ventricles has been attributed to the lack of angiotensin II receptors in this tissue. This indicates that, in addition to mechanical factors, circulating hormones which have in common the use of the phosphoinositol pathway, may activate the expression of genes coding for regulatory proteins. This may play a role in the genesis of both ventricular and aortic hypertrophy.