Enhanced Ca²+ influx through cardiac L-type Ca²+ channels maintains the systolic Ca²+ transient in early cardiac atrophy induced by mechanical unloading.

Cardiac atrophy as a consequence of mechanical unloading develops following exposure to microgravity or prolonged bed rest. It also plays a central role in the reverse remodelling induced by left ventricular unloading in patients with heart failure. Surprisingly, the intracellular Ca(2+) transients which are pivotal to electromechanical coupling and to cardiac plasticity were repeatedly found to remain unaffected in early cardiac atrophy. To elucidate the mechanisms underlying the preservation of the Ca(2+) transients, we investigated Ca(2+) cycling in cardiomyocytes from mechanically unloaded (heterotopic abdominal heart transplantation) and control (orthotopic) hearts in syngeneic Lewis rats. Following 2 weeks of unloading, sarcoplasmic reticulum (SR) Ca(2+) content was reduced by ~55 %. Atrophic cardiac myocytes also showed a much lower frequency of spontaneous diastolic Ca(2+) sparks and a diminished systolic Ca(2+) release, even though the expression of ryanodine receptors was increased by ~30 %. In contrast, current clamp recordings revealed prolonged action potentials in endocardial as well as epicardial myocytes which were associated with a two to fourfold higher sarcolemmal Ca(2+) influx under action potential clamp. In addition, Cav1.2 subunits which form the pore of L-type Ca(2+) channels (LTCC) were upregulated in atrophic myocardium. These data suggest that in early cardiac atrophy induced by mechanical unloading, an augmented sarcolemmal Ca(2+) influx through LTCC fully compensates for a reduced systolic SR Ca(2+) release to preserve the Ca(2+) transient. This interplay involves an electrophysiological remodelling as well as changes in the expression of cardiac ion channels.

Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11.

Familial hypertrophic cardiomyopathy (FHC) is a cardiac disorder transmitted as an autosomal dominant trait. FHC has been shown to be genetically heterogeneous with less than 50% of published pedigrees being associated with mutations in the beta myosin heavy chain (beta-MHC) gene on chromosome 14q11-q12. A second locus has recently been reported on chromosome 1. We examined the segregation of microsatellite markers in a French pedigree for which the disease is not linked to beta-MHC gene. We found significant linkage of the disease locus to several (CA)n repeats located on chromosome 11 (lod scores between +3.3 and +4.98). The data suggest the localization of the novel FHC gene in a region spanning 17 centiMorgans.

Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the interventricular septum and associated with a large extent of myocardial and myofibrillar disarray. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for beta-myosin heavy chain, cardiac troponin T and alpha-tropomyosin. Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins.

Altered myocardial gene expression reveals possible maladaptive processes in heterozygous and homozygous cardiac myosin-binding protein C knockout mice.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by left ventricular hypertrophy (LVH) predominantly affecting the interventricular septum. Cardiac myosin-binding protein C (cMyBP-C) mutations are common causes of FHC. Gene expression profiling was performed in left ventricles of 9-week-old wild-type mice, heterozygous cMyBP-C KO mice displaying asymmetric septal hypertrophy, and homozygous mice developing eccentric LVH. Knocking out one or two cMyBP-C genes leads primarily to gene expression changes indicating an increased energy demand, activation of the JNK and p38 parts of the MAPK pathway and deactivation of the ERK part, and induction of apoptosis. Altered gene expression for processes related to cardiac structure, contractile proteins, and protein turnover was also identified. Many of the changes were more pronounced in the homozygous KO mice. These alterations point to physiological and pathological adaptations in the prehypertrophic heterozygous KO mice and the hypertrophic homozygous mice.

The Role of Executive Functioning and Technological Anxiety (FOMO) in College Course Performance as Mediated by Technology Usage and Multitasking Habits.

This study investigated how technology use impacts academic performance. A proposed model postulated that academic performance could be predicted by a cognitive independent variable-executive functioning problems-and an affective independent variable-technological anxiety or FOMO (fear of missing out)-mediated by how students choose to use technology. An unobtrusive smartphone application called "Instant Quantified Self" monitored daily smartphone un-locks and daily minutes of use. Other mediators included self-reported smartphone use, self-observed studying attention, self-reported multitasking preference, and a classroom digital metacognition tool that assessed the student's ability to understand the ramifications of technology use in the classroom that is not relevant to the learning process. Two hundred sixteen participants collected an average of 56 days of "Instant" application data, demonstrating that their smartphone was unlocked more than 60 times a day for three to four minutes each time for a total of 220 daily minutes of use. Results indicated that executive functioning problems predicted academic course performance mediated by studying attention and a single classroom digital metacognition subscale concerning availability of strategies of when to use mobile phones during lectures. FOMO predicted performance directly as well as mediated by a second classroom digital metacognition concerning attitudes toward mobile phone use during lectures. Implications for college students and professors include increasing metacognition about technology use in the classroom and taking "tech breaks" to reduce technology anxiety.

Este estudio analiza la repercusión del uso de la tecnología en el desempeño académico. Se propuso un modelo que postulaba que el desempeño académico podía predecirse mediante una variable independiente cognitiva (los problemas de funcionamiento ejecutivo) y una variable independiente afectiva (la ansiedad tecnológica o FOMO ­el miedo a perderse algo), influido por el modo como los alumnos elegían utilizar la tecnología. Mediante una aplicación para móvil no intrusiva, denominada "Yo cuantificado instantáneo" seguía los desbloqueos diarios del móvil y los minutos de uso. Había otros mediadores, como el uso del móvil según el usuario, la atención en el estudio según la observa el usuario, preferencias de multi-tarea según el usuario y una nueva herramienta de medida digital en el aula para analizar la capacidad del alumno para entender las ramificaciones del uso de la tecnología en el aula que no relevante para el proceso de aprendizaje. Un total de 216 participantes recogieron datos de la aplicación "instantánea" durante una media de 56 días, mostrando que su teléfono móvil era desbloqueado más de 60 veces al día entre tres y cuatro minutos cada vez durante un total de 220 minutos diarios de uso. Los resultados indicaban que los problemas de funcionamiento ejecutivo predecían el rendimiento académico mediatizado por la atención en el estudio y una única subescala de metacognición digital en el aula relativa a la disponibilidad de estrategias sobre cuándo utilizar el móvil durante las clases. El FOMO predecía el desempeño directamente además de a través de una segunda metacognición digital del aula relativa a las actitudes hacia el teléfono móvil durante las clases. Entre las implicaciones para los alumnos y los profesores está el aumento de la metacognición sobre el uso de la tecnología en el aula y "descansar de la tecnología" para disminuir la ansiedad que produce.

Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts.

Expression of the two sarcomeric actins, alpha-skeletal and alpha-cardiac, is regulated in the rodent heart in response to developmental, hormonal, and hemodynamic stimuli. Little is known in man, except that both isogenes were found to be coexpressed in three adult ventricles. In this report, we investigated the isoactin mRNA composition in ventricles from 21 control patients (4 fetal, 5 juvenile, 12 adult) and from 15 patients undergoing cardiac transplantation (5 idiopathic dilated cardiomyopathies, 5 ischemic myopathies with myocardial infarcts, 5 diverse etiologies) by two different and complementary techniques: RNA dot blot analysis with specific cDNA probes, and primer extensions with an oligonucleotide common to alpha-cardiac and alpha-skeletal actins. In the case of dot blot analysis, quantification of each isoform was performed by using as standards RNA transcripts obtained from cloned human alpha-actin sequences, and the total amount of sarcomeric actin mRNA was evaluated as a function of total poly(A+)RNA. We found that both isogenes are always coexpressed, and that the isoactin pattern changes during development. In utero and in neonatal hearts, alpha-skeletal actin mRNA represents less than or equal to 20% of sarcomeric actins, it increases to 48 +/- 6% during the first decade after birth and becomes the predominant isoform of adult hearts (60.4 +/- 8.5%). The 15 adult failing hearts exhibited the same isoactin pattern as the control ones (62.84 +/- 11.06%), and there was no difference in expression between patients with dilated cardiomyopathy or ischemic heart disease. These observations demonstrate that cardiac development in man, in contrast to rodent heart, is characterized by an up-regulation of the skeletal actin gene, the expression of which does not change in hypertrophied and failing hearts, and suggest that the actin and myosin heavy chain families are independently regulated in human heart.

Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene.

Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetically heterogeneous disease. The first identified disease gene, located on chromosome 14q11-q12, encodes the beta-myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the beta-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, recently mapped to chromosome 14q11-q12. Significant linkage was found with MYO I and MYO II in pedigree 720, but results were not conclusive for pedigree 730. Haplotype analysis of the six markers allowed identification of affected individuals and of some unaffected subjects carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing, 403Arg-->Leu and 403Arg-->Trp in families 720 and 730, respectively. The 403Arg-->Leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the 403Arg-->Trp mutation appeared less severe. Haplotyping of polymorphic markers in close linkage to the beta-myosin heavy chain gene can, thus, provide rapid analysis of non informative pedigrees and rapid detection of carrier status. Our results also indicate that codon 403 of the beta-myosin heavy chain gene is a hot spot for mutations causing FHC.

Abnormal rapid Ca2+ release from sarcoplasmic reticulum of malignant hyperthermia susceptible pigs.

Using the rapid filtration technique to investigate Ca2+ movements across the sarcoplasmic reticulum (SR) membrane, we compare the initial phases of Ca2+ release and Ca2+ uptake in malignant hyperthermia susceptible (MHS) and normal (N) pig SR vesicles. Ca2+ release is measured from passively loaded SR vesicles. MHS SR vesicles present a 2-fold increase in the initial rate of calcium release induced by 0.3 microM Ca2+ (20.1 +/- 2.1 vs. 6.3 +/- 2.6 nmol mg-1 s-1). Maximal Ca2+ release is obtained with 3 microM Ca2+. At this optimal concentration, rate of Ca2+ efflux in absence of ATP is 55 and 25 nmol mg-1 s-1 for MHS and N SR, respectively. Ca(2+)-induced Ca2+ release is inhibited by Mg2+ in a dose-dependent manner for both MHS and N pig SR vesicles (K1/2 = 0.2 mM). Caffeine (5 mM) and halothane (0.01% v/v) increase the Ca2+ sensitivity of Ca(2+)-induced Ca2+ release. ATP (5 mM) strongly enhances the rate of Ca2+ efflux (to about 20-40-fold in both MHS and N pig SR vesicles). Furthermore, both types of vesicles do not differ in their high-affinity site for ryanodine (Kd = 12 nM and Bmax = 6 pmol/mg), lipid content, ATPase activity and initial rate of Ca2+ uptake (0.948 +/- 0.034 vs. 0.835 +/- 0.130 mumol mg-1 min-1 for MHS and N SR, respectively). Our results show that MH syndrome is associated to a higher rate of Ca2+ release in the earliest phase of the calcium efflux.

COOH-terminal truncated cardiac myosin-binding protein C mutants resulting from familial hypertrophic cardiomyopathy mutations exhibit altered expression and/or incorporation in fetal rat cardiomyocytes.

Mutations in human cardiac myosin-binding protein C (cMyBP-C) gene are associated with familial hypertrophic cardiomyopathy (FHC), and most of them are predicted to produce COOH-truncated proteins. To understand the molecular mechanism(s) by which such mutations cause FHC, we analyzed (i) the accumulation of human cMyBP-C mutants in fetal rat cardiomyocytes, and (ii) the protein sequence of the human wild-type (wt) cMyBP-C by hydrophobic cluster analysis with the aim of identifying new putative myosin-binding site(s). Accumulation and sarcomeric localization of the wt protein and of four FHC-mutant cMyBP-Cs (E542Q and three COOH-truncated proteins) were studied in cardiomyocytes by immunostaining and confocal microscopy after transfection with myc-tagged constructs. We found that: (i) 10 % of the cells expressing COOH-truncated mutants exhibit an incorporation into the A-band of the sarcomere without any alteration of the myofibrillar architecture versus 76 % of those expressing the wt or E542Q mutant cMyBP-Cs (p<0.001); (ii) 90 % of the cells expressing the truncated mutants show a diffuse localization of these proteins in the cardiomyocytes, out of which 45 % exhibit a significant alteration of the sarcomeric structure (p<0.0001 versus wt); and (iii) the two shortest mutant cMyBP-Cs accumulate at very low levels in fetal rat cardiomyocytes as compared to the wt (p<0.008). Protein sequence analysis indicated that a 45-residue sequence in the NH2-terminal C0 domain of cMyBP-C exhibits a consistent homology (sequence similarity score of 42 %) with a segment of the NH2-terminal domain of myomesin, another myosin-binding protein. This result suggests that the C0 domain of human cMyBP-C contains a novel putative myosin-binding site that could account for the A-band incorporation of the truncated mutants. In addition, the faint accumulation and the diffuse localization of truncated mutants could probably be explained by a low affinity of the C0 domain for myosin. We conclude that COOH-truncated cMyBP-Cs may act as poison polypeptides that disrupt the myofibrillar architecture and result in the defects observed in FHC.

G-protein dependent potentiation of calcium release from sarcoplasmic reticulum of skeletal muscle.

Skinned fibre experiments were conducted to determine if guanine nucleotide-binding proteins play a role in excitation-contraction coupling of skeletal muscle. By itself, the GTP-gamma S, a non hydrolysable GTP analogue was unable to induce calcium release from the sarcoplasmic reticulum, even at concentrations as high as 500 microM. However, calcium- or caffeine-induced calcium releases were enhanced by GTP-gamma S in micromolar concentrations. This response was blocked by GDP-beta S or Pertussis toxin. 32P-ADP-ribosylation catalysed by Pertussis toxin, radiolabelled G-protein alpha subunits in the range of 40 kDa on membrane subcellular fractions of rat skeletal muscle. Using Western blot analysis with antibodies raised against the bovine transducin, G-proteins were identified in frog and rat skeletal muscle subcellular fractions. In most of the muscle fractions (plasma membrane, T-tubules, triads, sarcoplasmic reticulum), the anti-beta subunit antibodies recognized a 36 kDa protein which comigrated with transducin beta subunit. It appears therefore that some of the G-proteins identified by ADP-ribosylation or immunostaining in several subcellular fractions from skeletal muscle, are implicated in the modulation of calcium release from sarcoplasmic reticulum. These results suggest that a Pertussis toxin sensitive G-protein is present at the loci of E-C coupling, and that it serves to regulate the calcium release.

Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy.

Five disease genes encoding sarcomeric proteins and associated with familial and classical forms of hypertrophic cardiomyopathy have been determined since 1989. In 1996 two other genes encoding ventricular regulatory and essential myosin light chains were shown to be associated with a particular phenotype of the disease characterized by mid left ventricular obstruction. The aim of the present study was to search for mutations in the ventricular regulatory myosin light chain gene (MYL2), located on chromosome 12q23q24.3, in a panel of 42 probands presenting a classical phenotype of familial hypertrophic cardiomyopathy. Single-strand conformation polymorphism analysis was used to search for mutations in the coding segments of the MYL2 gene, and the abnormal products were sequenced. Two novel missense mutations, Phe18Leu in exon 2 and Arg58Gln in exon 4 were identified in three unrelated families. None of the affected patients had hypertrophy localized only at the level of the papillary muscle with mid left ventricular obstruction. By analysis of genetic recombinations, one of these mutations identified in a large family allowed us to refine the localization of the MYL2 gene on the genetic map, in an interval of 6 cM containing six informative microsatellite markers. In conclusion, we show that mutations in the MYL2 gene may be involved in familial and classical forms of hypertrophic cardiomyopathy, and we provide new tools for the genetic analysis of patients with familial hypertrophic cardiomyopathy.

Genetic testing and genetic counselling in hypertrophic cardiomyopathy: the French experience.

AIMS: A major breakthrough in the molecular genetics of hypertrophic cardiomyopathy (HCM) has made genetic testing now available in clinical practice, raising new questions about its implications, potential benefits, and the organisation of the procedure. The aim of this work was (1) to discuss the different questions related to genetic testing in HCM, and propose guidelines for the different situations, (2) to report our preliminary experience with a specific procedure. METHODS AND RESULTS: The main questions asked by patients and relatives concern presymptomatic diagnosis and prenatal counselling/diagnosis, while clinicians sometimes discuss diagnostic and prognostic testing. To take into account the complex medical and psychological implications of this new approach, we developed a specific, multidisciplinary, and multiple step procedure, including a cardiologist, a geneticist, and a psychologist. Seventy subjects were examined, including (1) 29 adults for presymptomatic diagnosis (of whom 10 left the procedure after the first visit and 19 continued, among whom six had a mutation and two experienced negative psychological impact, observed during follow up), (2) nine couples of parents for presymptomatic diagnosis in their children (the procedure was stopped after the first visit in eight and continued in one), (3) 22 couples for prenatal counselling (no prenatal genetic testing was asked for after the first visit), and (4) 10 subjects for diagnostic testing. We decided to perform no prognostic testing. CONCLUSION: Our preliminary experience confirms the complexity of the situation and suggests the necessity for a specific procedure to ensure good practice in genetic testing of HCM.

Cardiac Myosin-binding protein C and hypertrophic cardiomyopathy.

The cardiac myosin-binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily; it has both structural and regulatory roles. The gene-encoding cardiac MyBP-C in humans is located on chromosome 11p11.2, comprises over 21,000 base pairs, and contains 35 exons. Mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy. Familial hypertrophic cardiomyopathy is an autosomal dominant disease characterized by ventricular hypertrophy associated with a large degree of myocardial and myofibrillar disarray. Most mutations found in the cardiac MyBP-C gene thus far are predicted to lead to an altered mRNA sequence and to produce the C-terminal truncation of the cardiac MyBP-C polypeptides lacking the myosin-binding site and also, in some cases, the titin-binding site. One might reasonably assume that the cardiac MyBP-C mutations exert their effect by altering the multimeric complex assembly of the cardiac sarcomere via the "null allele" mechanism, potentially leading to haploinsufficiency, and/or via a dominant negative effect of a misfolded RNA on the cardiac MyBP-C translation, which could interfere with the proper assembly of sarcomeric structures. These data underline the functional importance of MyBP-C in the regulation of cardiac work and provide the basis for further studies and for the production of transgenic animals for cardiac MyBP-C that will, one hopes, help to resolve the pathogenesis of chromosome-11-associated familial hypertrophic cardiomyopathy.

Budd-Chiari syndrome: typical and atypical scintigraphic aspects.

Budd-Chiari syndrome, a well known entity, is often difficult to diagnose, mostly due to the nonspecificity of its symptomatology. Radiocolloid liver scans were evaluated in eight cases of this disease, proven by surgical biopsy. Five cases showed the "classic" scintigraphic pattern of caudate lobe hypertrophy (62.5%), and other abnormalities observed included segmental hepatic insufficiency, diffuse hepatic insufficiency, and relative hypertrophy of both the caudate lobe and a portion of the parenchyma of segment VI (one case each). An experimental study of hepatic venous drainage performed on livers at autopsy revealed four groups of accessory hepatic veins in addition to the main hepatic veins. The occlusion of various parts of this drainage appears to relate to the various scintigraphic patterns that were encountered in patients with Budd-Chiari syndrome. A review of the literature revealed three additional patterns previously reported in association with Budd-Chiari syndrome (normal scan, diffuse hepatomegaly, and multiple filling defects). If all these variations are appreciated, liver scanning can be a valuable screening tool for Budd-Chiari syndrome and may also serve as a noninvasive means of follow-up.

Scintigraphic study of duodenal-gastric reflux in cases of primary gastropathy, chronic ulcer of the duodenal bulb, and Moynihan's disease.

There are several methods for detection of bile in the stomach, but none has proven satisfactory. It appears that the scintigraphic study with quantitation of duodenal-gastric reflux after corrections for the overlap of the stomach by the liver and bowel is more reliable, noninvasive, and physiologic. Fifty-four patients were divided into groups according to their clinical presentation; seven asymptomatic volunteers, 20 patients with duodenal-gastric reflux gastropathy (DRG), 16 patients with recurrent ulcers of the duodenal bulb (RUD), and 11 patients with Moynihan's disease. Each of the 47 dyspeptic patients underwent an endoscopic examination and a scintigraphic study with [99mTc]disofenin for detection and quantitation of duodenal-gastric reflux. Endoscopy revealed the presence of bile in the stomach of 16 out of 20 DRG and four out of 16 RUD, while ten out of 11 patients with Moynihan's disease had clear gastric juice. Most of the DRG cases (15 out of 20) and half of the RUD (eight out of 16) presented reflux greater than 1.5%, while of the 11 Moynhihan, ten presented reflux less than 1.5% and all the asymptomatic volunteer subjects less than 1%. This quantitation method allowed us to perceive clearly the low % of reflux in the "normal asymptomatic" subjects compared with the DRG-type of dyspeptic patients. Among the dyspeptic, the distinction seems more evident between the DRG type and the Moynihan type. Occasionally, the scintigraphic method permits identification of patients with slower gallbladder evacuation (eight out of 47 dyspeptic in our study), adding valuable information for the diagnostic approach to dyspeptic patients.

Extrahepatic uptake of technetium-99m-phytate: a prognostic index in patients with cirrhosis.

We examined the usefulness of technetium-99m-phytate (99mTc-phytate) hepatic scintigraphy in the evaluation of hepatic function, and the assessment of prognosis in patients with cirrhosis. Ninety-four patients with biopsy-documented cirrhosis had, at the time of entry into the study, a scintigraphy with 99mTc-phytate complexed with calcium in vivo. Extrahepatic uptake (EHU) of 99mTc-phytate on scintigraphy was graded from 0 (absent EHU) to 5 (important EHU) according to the relative distribution of the radiotracer between the liver, the spleen and the bone marrow. The severity of liver disease was also assessed according to the index of Child and Turcotte as modified by Pugh et al. Mean follow-up was 2 yr. EHU was correlated to the Pugh score (r = 0.73) and to survival. Survival at 2 yr was 97% for an EHU equal or inferior to 2.5, 62% for grades 3-4.5, and 31% for grade 5. In conclusion, hepatic imaging with 99mTc-phytate, in addition to its diagnostic value, also contains valuable prognostic information in patients with cirrhosis.

Effects of halothane on calcium release from sarcoplasmic reticulum of rabbit psoas and semitendinosus skinned muscle fibers.

Calcium release from sarcoplasmic reticulum was investigated using skinned fibers isolated from rabbit semitendinosus and psoas muscles, representative of slow and fast fibers, respectively. In both types of fibers, halothane at the concentration of 0.03% (v/v) enhanced the Ca2(+)-induced calcium release. In the absence of cytoplasmic free Ca2+, halothane induced calcium release in a dose-dependent manner, with a similar sensitivity for both semitendinosus and psoas fibers. These results are discussed in connection with muscular diseases such as malignant hyperthermia in which the crisis is triggered during anesthesia by halothane.

Prevalence of depression in Alzheimer's disease and validity of Research Diagnostic Criteria.

This study was undertaken to estimate the point-prevalence of Research Diagnostic Criteria (RDC) depressive syndromes in Alzheimer's disease (AD) and to evaluate the validity of existing and potential alternative diagnostic criteria for major depression in the presence of probable AD. Twenty-six subjects with probable AD of mild to moderate severity and their caregivers were interviewed to estimate the prevalence of RDC depressive syndromes. For the evaluation of the validity of RDC for major depression, an additional 8 probable-AD subjects with suspected depression were added to the sample. Sensitivity, specificity, and correlation with diagnosis of RDC major depression were calculated for each diagnostic criterion, and existing major depressive criteria were compared to potential alternative criteria currently used for RDC minor depression. Of the subjects in our prevalence sample, 15.4% were found to have major depression; 23.1%, minor depression; and 11.5%, intermittent depression. In our validation sample, two criteria for major depression, self-reproach/guilt and thinking/concentration difficulty, were weakly associated with the final diagnosis of major depression because of poor sensitivity or specificity. In contrast, three possible alternative criteria were significantly associated with the diagnosis of major depression and showed high sensitivity and specificity. These included nonverbal manifestations of depression, irritability/complaining, and demandingness/dependency. We conclude that RDC depressive syndromes are common in probable AD of mild to moderate severity. In the presence of AD, the validity of some existing major depressive criteria may be limited in comparison to several potential alternative criteria because of relatively poor sensitivity and/or specificity.

Depression in Alzheimer's disease: receiver operating characteristic analysis of the Cornell Scale for Depression in Dementia and the Hamilton Depression Scale.

This study compares the performance of the Cornell Scale for Depression in Dementia (CSDD) and the Hamilton Depression Scale (HDS) in detecting Research Diagnostic Criteria (RDC) major depression in subjects with mild-to-moderate Alzheimer's disease (AD). Thirty-four subjects with this diagnosis and their caregivers were interviewed. The senior author conducted a diagnostic interview to determine RDC diagnosis. An investigator, blind to diagnosis, obtained demographic information and administered the Mini Mental State Examination, Global Deterioration Scale, CSDD and HDS. For each depression scale, the correlation with the RDC diagnosis of major depression was calculated, as were the sensitivity and specificity at various cutoff scores. Nonparametric receiver operating characteristic analysis was used to compare the performance of the two scales. The area under the receiver operating characteristic curve was .91 for the CSDD and .87 for the HDS. This differed from chance to a highly significant degree for both the CSDD and the HDS but the difference between the two scales was not statistically significant. Although the precision of the present study is limited by the small sample size, a cutpoint of 7 provided reasonable performance for both the CSDD and the HDS, yielding a sensitivity of .90 for both scales and a specificity of .75 for the CSDD and 0.63 for the HDS. Although the CSDD and the HDS are rating scales rather than diagnostic instruments, receiver operating characteristic analysis indicates that both demonstrate statistically significant discriminating ability for RDC major depression in mild to moderate, probable AD.(ABSTRACT TRUNCATED AT 250 WORDS)

Attentional limits in memory retrieval.

The hypothesis that episodic memory retrieval can occur in parallel with other cognitive processes was tested in 2 experiments. Participants memorized words and then performed speeded cued recall (Experiment 1) or speeded yes-no recognition (Experiment 2) in a dual-task situation. The psychological refractory period design was used: The participant was presented with a single test item at various stimulus onset asynchronies (SOAs; 50-1,200 ms) after a tone was presented in an auditory-manual 2-alternative choice reaction task. Reducing the SOA increased the memory task reaction times. This slowing was additive with the effect of variables slowing retrieval in the memory task. The results indicate that memory retrieval is delayed by central processes in the choice task, arguing that the central bottleneck responsible for dual-task interference encompasses memory retrieval as well as response selection.