Calsequestrin determines the functional size and stability of cardiac intracellular calcium stores: Mechanism for hereditary arrhythmia

Calsequestrin is a high-capacity Ca-binding protein expressed inside the sarcoplasmic reticulum (SR), an intracellular Ca release and storage organelle in muscle. Mutations in the cardiac calsequestrin gene (CSQ2) have been linked to arrhythmias and sudden death. We have used Ca-imaging and patch-clamp methods in combination with adenoviral gene transfer strategies to explore the function of CSQ2 in adult rat heart cells. By increasing or decreasing CSQ2 levels, we showed that CSQ2 not only determines the Ca storage capacity of the SR but also positively controls the amount of Ca released from this organelle during excitation-contraction coupling. CSQ2 controls Ca release by prolonging the duration of Ca fluxes through the SR Ca-release sites. In addition, the dynamics of functional restitution of Ca-release sites after Ca discharge were prolonged when CSQ2 levels were elevated and accelerated in the presence of lowered CSQ2 protein levels. Furthermore, profound disturbances in rhythmic Ca transients in myocytes undergoing periodic electrical stimulation were observed when CSQ2 levels were reduced. We conclude that CSQ2 is a key determinant of the functional size and stability of SR Ca stores in cardiac muscle. CSQ2 appears to exert its effects by influencing the local luminal Ca concentration-dependent gating of the Ca-release channels and by acting as both a reservoir and a sink for Ca in SR. The abnormal restitution of Ca-release channels in the presence of reduced CSQ2 levels provides a plausible explanation for ventricular arrhythmia associated with mutations of CSQ2.     

Genetic variation in the 22q11 locus and susceptibility to schizophrenia

An increased prevalence of microdeletions at the 22q11 locus has been reported in samples of patients with schizophrenia. 22q11 microdeletions represent the highest known genetic risk factor for the development of schizophrenia, second only to that of the monozygotic cotwin of an affected individual or the offspring of two schizophrenic parents. It is therefore clear that a schizophrenia susceptibility locus maps to chromosome 22q11. In light of evidence for suggestive linkage for schizophrenia in this region, we hypothesized that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to approximately 2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers (average one single nucleotide polymorphism20 kb over 1.5 Mb) in the vicinity of the 22q11 locus, in both family- and population-based samples, we present here results consistent with this assumption. Moreover, our results are consistent with contribution from more than one gene to the strikingly increased disease risk associated with this locus. Finer-scale haplotype mapping has identified two subregions within the 1.5-Mb locus that are likely to harbor candidate schizophrenia susceptibility genes.     

Sleep apnea syndrome: improved detection of respiratory events and cortical arousals using oxymetry pulse wave amplitude during polysomnography

Respiratory events (RE) during sleep induce cortical arousals (A) and marked changes in autonomic markers in sleep apnea syndrome (SAS). The aims of the study were double. First, we assessed whether pulse wave amplitude (PWA) added to polysomnography (PSG) could improve RE and A detection; second, we wanted to know whether the quality of detection of these two parameters could be improved using PWA. Respiratory disturbance index (RDI) and A were randomly scored twice by the same observer in 12 male patients with SAS. The first scoring was done using conventional PSG signals, the second scoring adding PWA to PSG. We also measured interobserver agreement by randomly selecting and reading 100 PSG sequences of 5 min with and without PWA by two observers. Adding PWA to PSG parameters allowed to detect significantly more RDI (53.9 ± 21.6 h⁻¹ versus 48.3 ± 22.3 h⁻¹, p < 0.001) and more A (68.0 ± 14.4 versus 59.4 ± 16.5, p < 0.001). Moreover, after using PWA, there was no significant disagreement between two observers for detecting RE, showing better quality of RE detection. PWA is a simple and cheap parameter that improves the diagnostic value of conventional PSG in sleep apnea syndrome by better detecting respiratory events and A.     

High-frequency mutation at the adenine phosphoribosyltransferase locus in Chinese hamster ovary cells due to deletion of the gene.

Evidence for a two-step model to explain the high-frequency expression of the recessive phenotype at the autosomal adenine phosphoribosyltransferase (APRT; EC 2.4.2.7) locus in Chinese hamster ovary (CHO) cells was given by Simon et al. [Simon, A. E., Taylor, M. W., Bradley, W. E. C. & Thompson, L. (1982) Mol. Cell. Biol. 2, 1126-1133]. This model proposed a high-frequency event, leading to allelic inactivation or a loss of gene function, and a low-frequency event, causing a structural alteration of the APRT protein. Either event could occur first, resulting in two classes of heterozygotes. We have analyzed the low-frequency event that gave rise to the class 2 aprt heterozygote D416 and the high-frequency event that led to APRT- cells derived from D416. Genomic Southern blots of Msp I- or Hpa II-digested DNA from wild-type CHO, aprt heterozygote D416, and two APRT- cell lines derived from D416 indicate a loss of a specific Msp I/Hpa II recognition sequence at one aprt locus in the heterozygote that correlates with the production of the electrophoretically altered APRT protein found in D416. The APRT- mutants are homozygous for the loss of this Msp I/Hpa II site. By using an additional CHO gene as an internal control, it was determined that the APRT- mutants contain only a single copy of the altered aprt gene. Thus, the high-frequency event that produces APRT- mutants derived from D416 is not an inactivation event but rather a deletion of the wild-type aprt gene.     

Rotational ablation of chronic coronary occlusions

Rotational ablation was performed successfully in three chronic coronary occlusions. At 3 months follow-up, two of the three lesions were patent. These cases illustrate the overall advantages and unique technical aspects of this device.     

Mechanisms of exercise-induced asthma

In a previous review in this journal McFadden eloquently presented the findings which led him and his colleagues to propose that respiratory heat loss and the subsequent cooling of the airways are the initial reaction sequence leading to airway obstruction in hyperventilation and exercise-induced asthma [62]. He further concluded that: “Exercise per se is not essential and serves only as means to increase ventilation”. Our interpretation of currently available data has led us to conclude that while respiratory heat loss may play an important permissive role in initiating the bronchoconstriction which follows exercise, the weight of evidence indicates that exercise per se serves as the trigger mechanism and is not just a tool to increase ventilation. Moreover, we believe that the role of exercise in releasing chemical mediators has been established, although pathways by which the airway smooth muscle is affected are still uncertain.     

Isolated systolic hypertension in uremic hemodialyzed patients]

Prevalence of Isolated Systolic Hypertension (ISH) defined as systolic blood pressure greater than 160 mmHg and diastolic blood pressure less than 90 mmHg was studied in a population of 148 patients treated by hemodialysis whose 80 had undergone ambulatory blood pressure (ABP) recording during the interdialytic period. All patients were treated 3 times 4 hours a week. ABP was recorded for 48 hours between two sessions of hemodialysis using a Delmar Avionic Presurometer (PIV). Prevalence of ISH was 12.5%, while that of systolic-diastolic hypertension (SDH) was 15%. Average age at the time of the study was respectively 59 +/- 13 yrs ISH and 49 +/- 11 yrs SDH (p less than 0.01) while that of patients with normal blood pressure (N) was 57 +/- 10 yrs. Mean duration of HD treatment was no different between groups: 5.3 +/- 3.5 yrs ISH, 5.0 +/- 4.2 yrs SDH and 5.0 +/- 4.3 yrs N. Causes of end-stage renal disease were similar in each group. All patients with ISH and SDH and 42% of N pts were receiving antihypertensive treatment at the time of ABP recording. Finally, level of anemia and percentage of patients treated by EPO were similar in each group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulse wave analysis of the aortic pressure waveform in patients with vasovagal syncope

Vascular reflex mechanisms contribute to vasovagal syncope. However, the alterations in central haemodynamics in patients with vasovagal syncope are unknown. 30 consecutive patients (36.5 ± 15 years, 14 females) with recurrent vasovagal syncope (VVS) and a positive tilt table test were compared to 39 age- and sex-matched controls (36.9 ± 16 years, 15 females) with a negative tilt table result and no history of syncope. Central aortic pressure parameters including augmentation index and central pulse pressure as markers of aortic stiffness were generated non-invasively by applanation tonometry of the radial artery and use of a validated mathematical transfer function. No difference in aortic augmentation index was observed between groups. (VVS 9 ± 2.6 vs. Control 11 ± 2.4, p = 0.8). However, in patients with vasovagal syncope the aortic pressure waveform significantly differed from healthy controls. A prolonged time to the peak of aortic pressure wave (aortic T2) was observed in patients with vasovagal syncope (226 ± 24 vs. 208 ± 21 ms, p = 0.001). Furthermore time to the first shoulder of the aortic pressure wave (aortic T1) was slightly shorter compared to healthy controls, but did not reach statistical significance (106 ± 22 vs. 110 ± 12 ms, p = 0.33). Patients with vasovagal syncope have an altered aortic pressure waveform at rest, but no signs of elevated aortic stiffness. The underlying mechanisms for these findings may potentially result from a complex imbalance of the autonomic nervous system with a continuous deregulation of the sympathetic and parasympathetic reflex arcs.