Abnormal calcium signaling and sudden cardiac death associated with mutation of calsequestrin

Mutations in human cardiac calsequestrin (CASQ2), a high-capacity calcium-binding protein located in the sarcoplasmic reticulum (SR), have recently been linked to effort-induced ventricular arrhythmia and sudden death (catecholaminergic polymorphic ventricular tachycardia). However, the precise mechanisms through which these mutations affect SR function and lead to arrhythmia are presently unknown. In this study, we explored the effect of adenoviral-directed expression of a canine CASQ2 protein carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation D307H (CASQ2(D307H)) on Ca2+ signaling in adult rat myocytes. Total CASQ2 protein levels were consistently elevated approximately 4-fold in cells infected with adenoviruses expressing either wild-type CASQ2 (CASQ2(WT)) or CASQ2(D307H). Expression of CASQ2(D307H) reduced the Ca2+ storing capacity of the SR. In addition, the amplitude, duration, and rise time of macroscopic I(Ca)-induced Ca2+ transients and of spontaneous Ca2+ sparks were reduced significantly in myocytes expressing CASQ2(D307H). Myocytes expressing CASQ2(D307H) also displayed drastic disturbances of rhythmic oscillations in [Ca2+]i and membrane potential, with signs of delayed afterdepolarizations when undergoing periodic pacing and exposed to isoproterenol. Importantly, normal rhythmic activity was restored by loading the SR with the low-affinity Ca2+ buffer, citrate. Our data suggest that the arrhythmogenic CASQ2(D307H) mutation impairs SR Ca2+ storing and release functions and destabilizes the Ca2+-induced Ca2+ release mechanism by reducing the effective Ca2+ buffering inside the SR and/or by altering the responsiveness of the Ca2+ release channel complex to luminal Ca2+. These results establish at the cellular level the pathological link between CASQ2 mutations and the predisposition to adrenergically mediated arrhythmias observed in patients carrying CASQ2 defects.     

Obstetric adversity and age at first presentation with schizophrenia: evidence of a dose-response relationship

OBJECTIVE: The purpose of the study was to determine if a dose-response relationship exists between obstetric adversity and age at first presentation with schizophrenia. METHOD: The Dublin Psychiatric Case Register was used to identify subjects with schizophrenia. Data on obstetric complications, social class of origin, and family history of psychiatric illness were obtained for those subjects. RESULTS: A total of 409 patients with ICD-9 schizophrenia were identified. Patients with a history of obstetric complications presented earlier to psychiatric services. As the number of complications increased, the mean age at first presentation decreased. This effect was independent of social class of origin and family history of psychiatric illness. CONCLUSIONS: Obstetric adversity exerts an independent influence on the age at first presentation with schizophrenia, in a dose-response manner. This finding supports the existence of a causal relationship between obstetric adversity and age at first presentation with schizophrenia.     

Detection of in-stent restenosis of coronary stents using 40-detector row computed tomography in vitro

OBJECTIVE: To evaluate the performance of 40-detector row computed tomography (CT) in the detection of in-stent stenosis of coronary stents. METHODS: Seven patent vascular models, 7 stenotic models, and 7 obstructed models were scanned with a 40-detector CT. We made the vascular models using 3 types of stent (Bx-Velocity, Express2, Driver) with an inner diameter of about 2.5, 3.0, or 3.5 mm. We measured the stent lumen diameter and evaluated the in-stent stenosis visually for the 21 vascular models. We evaluated attenuation values of the stent lumen of the 9 patent models of 2.5-mm diameter. RESULTS: The inner diameters of the vascular models were underestimated by CT with mean measurement errors of -1.19 to -1.49 mm. The absolute mean overall measurement error decreased as the inner diameter increased. The direct visualization of in-stent stenosis was possible for the 3.0- and 3.5-mm diameter models, but impossible for the 2.5-mm diameter models. For patent vascular models of 2.5-mm diameter, the CT attenuation inside the stent was significantly higher than that of the unstented portion (P < 0.0001). For obstructed vascular models of 2.5-mm diameter, the CT attenuation inside the stent was significantly lower than that of the unstented portion (P < 0.0001). Also for stenotic vascular models of 2.5-mm diameter, the CT attenuation inside the stent was lower than that of the unstented portion. CONCLUSIONS: Visualization of stent lumen on CT is affected by the stent diameter. Measurement of stent lumen is useful for detection of in-stent stenosis, when the direct visualization of in-stent stenosis is impossible.     

A study on mRNA expressions of fibronectin in dermal and cerebral wound healing for wound age estimation

We investigated mRNA expressions of fibronectin for wound age estimation during dermal and cerebral wound healing. Fibronectin mRNA expressions in the injured skin peaked at 8h post-injury. The expressions were detected in endothelial cells before and after injury, whereas they were detectable in the epidermal cells at 1-240 h, in fibroblasts at 1-72 h, in neutrophils and macrophages at 8-72 h, respectively. However, the expressions in epidermal cells became relatively weak in the subacute phase. Fibronectin mRNA expressions of the injured cerebrum increased after the intervention and peaked at 48 h, whereas there was a slight decrease during 24h post-injury. Although fibronectin mRNA was seen exclusively in the endothelial cells of the intact cerebrum, it was also detected in astrocytes during wound healing. From these findings, it was considered that fibronectin played an important role in dermal and cerebral wound healing. Expression of fibronectin mRNA was considered to indicate the acute phase of dermal wound healing, and the subacute phase of cerebral wound healing.     

Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population

OBJECTIVE: Advanced paternal age at birth as a risk for schizophrenia in the adult offspring has been reported in previous studies exclusively conducted in Western countries and Israel. The question has arisen whether this finding could be replicated in countries with socially and culturally different attitudes toward marriage, including factors such as age at marriage. To address this question, we conducted a case-control study of a Japanese population. METHODS: The subjects were representative inpatients with a DSM-IV diagnosis of schizophrenia. Unrelated healthy volunteers were recruited as control subjects. This study was conducted as one of a series of the projects by use of "The Mother and Child Health Handbooks (MCHHs)," from which information on parental characteristics around the time of birth, including parental ages at birth, had been extracted and recorded on computer. RESULTS: Ninety-nine subjects with schizophrenia and 381 healthy control subjects enrolled for the study. Advanced paternal, but not maternal, age was associated with an elevated risk for schizophrenia. Reproducibility of the association across different cultures is suggestive of a causal link.     

Influences of environmental noise level and respiration rate on the accuracy of acoustic respiration rate monitoring

We tested the hypothesis that the environmental noise generated by a forced-air warming system reduces the monitoring accuracy of acoustic respiration rate (RRa). Noise levels were adjusted to 45–55, 56–65, 66–75, and 76–85 dB. Healthy participants breathed at set respiration rates (RRset) of 6, 12, and 30/min. Under each noise level at each RRset, the respiration rates by manual counting (RRm) and RRa were recorded. Any appearance of the alarm display on the RRa monitor was also recorded. Each RRm of all participants agreed with each RRset at each noise level. At 45–55 dB noise, the RRa of 13, 17, and 17 participants agreed with RRset of 6, 12, and 30/min, respectively. The RRa of 14, 17, and 16 participants at 56–65 dB noise, agreed with RRset of 6, 12, and 30/min, respectively. At 66–75 dB noise, the RRa of 9, 15, and 16 participants agreed with RRset of 6, 12, and 30/min, respectively. The RRa of one, nine, and nine participants at 76–85 dB noise agreed with RRset of 6, 12, and 30/min, respectively, which was significantly less than the other noise levels (P?<?0.05). Overall, 72.9% of alarm displays highlighted incorrect values of RRa. In a noisy situation involving the operation of a forced-air warming system, the acoustic respiration monitoring should be used carefully especially in patients with a low respiration rate.