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Introduction: Disturbances of circadian rhythms occur in all episodes of bipolar disorder (BD). Lithium, as gold-standard in the maintenance treatment of BD, is known to influence circadian processes. Methods: In a pilot study lymphoblastoid cell lines (LCLs) were generated from 8 BD patients and 6 healthy controls. The LCLs were treated with lithiumchloride (LiCl) for 3 weeks. Cell cycles were then synchronized and expressional analysis by quantitative Real Time PCR was done. Results: BD and controls differed in the period length regarding DBP (albumin D-box binding protein) expression and DBP expression was also influenced by lithium treatment. Furthermore, baseline DBP expression was significantly different between non-treated BD and healthy controls. None of the other analyzed circadian genes showed to be influenced by chronic lithium treatment or to be differentially regulated due to the diagnosis. Discussion: We here show that chronic lithium treatment of LCLs leads to decreased expression of the clock gene DBP, rendering DBP a lithium-regulated gene. We could confirm the role of the circadian clock as well in lithium mode of action as in the pathomechanisms of BD although future studies with a greater number of participants and cell lines are needed.

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes in antigen-dependent B-cell maturation. SHM is not restricted to immunoglobulin gene loci, raising the possibility of a function for AID in other cell types. In this study, it is shown that AID is expressed in spermatocytes in the human testis. AID was mostly cytoplasmic but nuclear AID was also observed in a proportion of cells, in keeping with the DNA deamination model of AID function. Intratubular germ cell neoplasia unclassified (IGCNU), the precursor lesion of testicular cancers, was AID-negative. Seminomas also lacked AID expression. Nuclear and cytoplasmic AID expression was observed in three of 32 mixed non-seminomatous germ cell tumours. The results provide evidence for a physiological role for AID outside the immune system. AID expression in spermatocytes points to a role in meiosis. It remains uncertain whether AID may also contribute to the genetic aberrations characteristically found in testicular germ cell tumours. The consistent absence of detectable AID expression in atypical spermatogonia of IGCNU and its rare expression in germ cell tumours suggest that continued expression of AID is not involved in the pathogenesis of germ cell tumours.

Protein aggregation is an important field of investigation because it is closely related to the problem of neurodegenerative diseases, to the development of biomaterials, and to the growth of cellular structures such as cyto-skeleton. Self-aggregation of protein amyloids, for example, is a complicated process involving many species and levels of structures. This complexity, however, can be dealt with using statistical mechanical tools, such as free energies, partition functions, and transfer matrices. In this article, we review general strategies for studying protein aggregation using statistical mechanical approaches and show that canonical and grand canonical ensembles can be used in such approaches. The grand canonical approach is particularly convenient since competing pathways of assembly and dis-assembly can be considered simultaneously. Another advantage of using statistical mechanics is that numerically exact solutions can be obtained for all of the thermodynamic properties of fibrils, such as the amount of fibrils formed, as a function of initial protein concentration. Furthermore, statistical mechanics models can be used to fit experimental data when they are available for comparison., Comment: Accepted to IJMS

Under Decision 2119/98/EC of the European Parliament and of the Council, a network for epidemiological surveillance and control of communicable diseases in the Community was set up in 1998. One pillar of Decision 2119/98/EC is the early warning and response system (EWRS). The main objective of the network is to establish permanent communication between European Union (EU) Member States’ public health authorities, which are responsible for determining the measures required to control communicable disease-related events. Since 1998, a web based informatics tool has been developed in order to allow information to be shared between the relevant public health authorities. Between 1998 and December 2005, a total of 583 messages were circulated through the EWRS, notifying 396 events. The information shared through the system helped to coordinate public health measures in the EU. However, only few events prompted specific measures at Community level and most of them were controlled with public health measures applied at national level. Major events (such as the Severe Acute Respiratory Syndrome) and the results of simulation exercises prompted the Commission to upgrade the informatics system on the basis of user needs. Since 1 May 2004 the 10 newest Member States have provided information under the current legislation and since April 2005 the European Centre for Disease Prevention and Control (ECDC) is part of the system. Future developments will include a link between the existing EWRS and the communication platform currently developed by the ECDC.

Left ventricular (LV) dP/dt is considered an important hemodynamic factor influencing the dynamics of mechanical heart valve prostheses. LV dP/dt is dependent on patient factors including age, cardiac activity, health, and medication. The objective of this study was to determine the effect of LV dP/dt on the closing dynamics of mechanical heart valve prostheses in the mitral position. Eight instrumented 29 mm Björk-Shiley Convexo-Concave (BSCC) heart valves were tested in the pulse duplicator of the Helmholtz Institute. The valves had miniature strain gages mounted at the base of the outlet strut to measure impact loads at closure. Closing velocities were measured with a "light gate" device which was triggered by the closing leaflet. Physiologic pressure and flow waveforms were generated by a computer-controlled hydraulic drive unit. LV dP/dt was varied from 500 to 4000 mmHg/s simulating a wide range of physiologic conditions. It was found that the closing velocity was almost linearly related to LV dP/dt. At 4000 mmHg/s, closing velocities ranged from 1.5 to 2.0 m/s. Impact loads increased monotonically with LV dP/dt and closing velocity. In some valves, impact loads reached 2800 g at LV dP/dt of 4000 mmHg/s, and closing velocities of 2.0 m/s.

The purpose of this study was to determine analytically the hemodynamic factors that affect the closing velocity of the disc of Björk-Shiley convexo-concave (BSCC) prosthetic mitral valves. The motion of the BSCC disk was modelled by Newton's second law written in the form of a second order differential equation which expressed the instantaneous angle of the disc with respect to the valve ring as a function of the instantaneous pressure drop across the mitral valve, delta P(t), and the angle of the pressure gradient vector acting upon the disc during closure. The disc closes in response to the negative pressure drop created by the crossover of left atrial and left ventricular (LV) pressures. The rate of closure depends on the rate of development of the pressure drop across the valve, d delta P/dt, which is largely dependent upon the rate of change of left ventricular pressure during isovolumic contraction, LV dP/dt. The closure rate is also strongly dependent on the initial angle of the pressure drop vector with respect to the disc. The disc was predicted to reach its highest velocity at the moment of impact, based on the Runge-Kutta solution. Modelling suggests that a high LV dP/dt during valve closure or distorted LV geometry, causing the angle between the fully open disc and the pressure drop vector to shift, will cause the valve to have a high velocity at the moment of impact and may produce high impact loads.

Previous studies have shown that exposure of HeLa cells stably transfected with an HIV-long terminal repeat-chloramphenicol acetyltransferase (HIV-LTR-CAT) construct to many DNA-damaging agents (such as UV light) induces expression from the HIV LTR. By culturing the cells with salicylic acid we demonstrated dose-dependent repression of this UV-or cis-platinum (cis-Pt)-induced HIV expression. While salicylic acid treatment, indomethacin treatment, UV exposure, or cis-Pt treatment alone decreased viability by up to 50%, equal numbers of viable cells were used for the CAT assays. Repression was evident if salicylic acid was administered 2 h before, at the same time as, or up to 6 h after exposure to the DNA-damaging agent. The kinetics were similar for UV- and for cis-Pt-induced HIV expression, and induction was dependent on the UV dose or cis-Pt concentration added to the culture. pH changes of the media alone in the absence of salicylic acid did not affect HIV expression. Indomethacin (100 microM) did not affect UV- or cis-Pt-induced HIV expression. These results suggest a role for the prostaglandins or the cyclo-oxygenase pathway or both in HIV induction mediated by DNA-damaging agents.

Previous work by our group and others has shown the modulation of human immunodeficiency virus (HIV) promoter or long terminal repeat (LTR) after exposure to neutrons and ultraviolet radiations. Using HeLa cells stably transfected with a construct containing the chloramphenicol acetyl transferase (CAT) gene, the transcription of which is mediated by the HIV-LTR, we designed experiments to examine the effects of exposure to different types of radiation (such as gamma rays, ultraviolet and sunlight irradiations, electromagnetic fields and microwaves) on HIV-LTR-driven expression of CAT. These results demonstrated ultraviolet-light-induced transcription from the HIV promoter, as has been shown by others. Exposure to other DNA-damaging agents such as gamma rays and sunlight (with limited exposures) had no significant effect on transcription mediated by HIV-LTR, suggesting that induction of HIV is not mediated by just any type of DNA damage but rather may require specific types of DNA damage. Microwaves did not cause cell killing when cells in culture were exposed in high volumes of medium, and the same cells showed no changes in expression. When microwave exposure was carried out in low volumes of medium (so that excessive heat was generated) induction of HIV-LTR transcription (as assayed by CAT activity) was evident. Electromagnetic field exposures had no effect on expression of HIV-LTR. These results demonstrate that not all types of radiation and not all DNA-damaging agents are capable of inducing HIV. We hypothesize that induction of HIV transcription may be mediated by several different signals after exposure to radiation.

The relationship between the pressure losses within the nasal airways and nasal geometry were studied in a 3:1 scale model. The geometry of the model was based on magnetic resonance images of the skull of a healthy male subject. Pressure measurements, flow visualization, and hot-wire anemometry studies were performed at flow rates that, in vivo, corresponded to flows of between 0.05 and 1.50 l/s. The influence of nasal congestion and the collapse of the external nares were examined by using modeling clay to simulate local constrictions in the cross section. A dimensionless analysis of the pressure losses within three sections of the airway revealed the influence of various anatomic dimensions on nasal resistance. The region of the exterior nose behaves as a contraction-expansion nozzle in which the pressure losses are a function of the smallest cross-sectional area. Losses in the interior nose resemble those associated with channel flow. The nasopharynx is modeled as a sharp bend in a circular duct. Good correspondence was found between the predicted and actual pressure losses in the model under conditions that stimulated local obstructions and congestion.

Despite the common use of the standard 12-lead ECG, its reliability as an indicator of coronary artery disease (CAD) is poor. The normal ECG is falsely negative in more than 50% of angiographically proven CAD. The waveform of the standard ECG, however, can be transformed mathematically by nonlinear signal transformation to enhance its interpretation by computer. Using such a process it is possible that abnormalities can be identified in "normal" ECGs that can be correlated with CAD, thus identifying high-risk patients. A computer template that represents grouped data of normal ECGs for patients who also have normal coronary angiography was developed. Unblinded, preliminary testing of the template on normal ECGs of 107 white patients who had normal or abnormal coronary angiograms was performed. The process identified presence or absence of CAD with 82% specificity and 71% sensitivity for 53 women, and with 82% specificity and 86% sensitivity for 54 men. These preliminary results are promising, but further refinement of the templates is required and blinded studies with larger numbers and varieties of patients are needed.

In order to enhance subtle changes not apparent in resting ECGs by conventional criteria, a computerized signal processing technique, biopotential coordinate transformation (BCT), has been developed to increase the physician's perceptibility of CAD in seemingly "normal" resting ECGs. ECGs initially read as normal then can be tested with this process to predict the presence or absence of CAD. A blinded, retrospective study of 93 Caucasian patients with normal ECGs was performed using coronary angiography as the test standard. The BCT process identified the presence or absence of CAD with an 84.3% sensitivity and 81.8% specificity in 62 men. Similarly, a 76.2% sensitivity and 80% specificity was obtained for 31 women. These results suggest that the BCT process may provide the emergency physician with a noninvasive screening test for the detection of CAD in patients with apparently normal resting ECGs. Further studies are necessary for process refinement and verification.