Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

Endogenous motion of liver correlates to the severity of portal hypertension

BACKGROUND Degree of portal hypertension(PH) is the most important prognostic factor for the decompensation of liver cirrhosis and death, therefore adequate care for patients with liver cirrhosis requires timely detection and evaluation of the presence of clinically significant PH(CSPH) and severe PH(SPH). As the most accurate method for the assessment of PH is an invasive direct measurement of hepatic venous pressure gradient(HVPG), the search for non-invasive methods to diagnose these conditions is actively ongoing.AIM To evaluate the feasibility of parameters of endogenously induced displacements and strain of liver to assess degree of PH.METHODS Of 36 patients with liver cirrhosis and measured HVPG were included in the casecontrol study. Endogenous motion of the liver was characterized by derived parameters of region average tissue displacement signal(dantero, dretro, d RMS) and results of endogenous tissue strain imaging using specific radiofrequency signal processing algorithm. Average endogenous strain μ and standard deviation σ of strain were assessed in the regions of interest(ROI)(1 cm × 1 cm and 2 cm × 2 cm in size) and different frequency subbands of endogenous motion(0-10 Hz and 10-20 Hz).RESULTS Four parameters showed statistically significant(P 0.05) correlation with HVPG measurement. The strongest correlation was obtained for the standard deviation of strain(estimated at 0-10 Hz and 2 cm × 2 cm ROI size). Three parameters showed statistically significant differences between patient groups with CSPH, but only dretro showed significant results in SPH analysis. According to ROC analysis area under the curve(AUC) of the σROI[0…10 Hz, 2 cm × 2 cm] parameter reached 0.71(P = 0.036) for the diagnosis of CSPH; with a cut-off value of 1.28 μm/cm providing 73% sensitivity and 70% specificity. AUC for the diagnosis of CSPH for μROI[0…10 Hz, 1 cm × 1 cm] was 0.78(P = 0.0024); with a cut-off value of 3.92 μm/cm providing 73% sensitivity and 80% specificity. Dretro parameter had an AUC of 0.86(P = 0.0001) for the diagnosis of CSPH and 0.84(P = 0.0001) for the diagnosis of SPH. A cut-off value of-132.34 μm yielded 100% sensitivity for both conditions, whereas specificity was 80% and 72% for CSPH and SPH respectively.CONCLUSION The parameters of endogenously induced displacements and strain of the liver correlated with HVPG and might be used for non-invasive diagnosis of PH.     

Longitudinal gradient coil optimization in the presence of transient eddy currents.

The switching of magnetic field gradient coils in magnetic resonance imaging (MRI) inevitably induces transient eddy currents in conducting system components, such as the cryostat vessel. These secondary currents degrade the spatial and temporal performance of the gradient coils, and compensation methods are commonly employed to correct for these distortions. This theoretical study shows that by incorporating the eddy currents into the coil optimization process, it is possible to modify a gradient coil design so that the fields created by the coil and the eddy currents combine together to generate a spatially homogeneous gradient that follows the input pulse. Shielded and unshielded longitudinal gradient coils are used to exemplify this novel approach. To assist in the evaluation of transient eddy currents induced within a realistic cryostat vessel, a low-frequency finite-difference time-domain (FDTD) method using the total-field scattered-field (TFSF) scheme was performed. The simulations demonstrate the effectiveness of the proposed method for optimizing longitudinal gradient fields while taking into account the spatial and temporal behavior of the eddy currents.     

非胰岛素依赖型糖尿病患者血清唾液酸的改变

测定20例NIDDM伴有心脑血管病变的患者、20例单纯NIDDM患者的血清唾液酸（SA）水平，并与20例正常人进行比较。结果发现所有NIDDM患者的血清SA水平均显著增高（P＜0．01），其中伴有心脑血管疾病患者的血清SA水平显著高于单纯NIDDM患者（P＜0．05），同时血清SA水平与血清胰岛素及C肽水平、收好压之间存在相关。提示血清SA水平与NIDDM患者的心脑血管疾病关系密切，可能是心脑血管并发症发生的一个危险因素。     

Responses of CDKs and p53 in Delayed Ischemic Neuronal Death

Stroke is a debilitating disease that affects millions each year.While in many cases cerebral ischemic in jury can be limited by effectivw resuscitation or thrombolytic treatment,the injured neurons wither in a process known as delayed neuronal death(DND).Mounting evidence indicates that DND is not simply necrosis played out in slow motion but apoptosis is triggered.Of particular interest are two groups of signal proteins that participate in apoptosis-cyclin dependent kinases(CDKs) and p53-among a myriad of signaling events after an ischemic insult.Recent investigations have shown that CDKs,a family of enzymes initially known for their role in cell cycle regulation,are activated in injured neurons in DND.As for p53,new reports suggest that its up-regulation may represent a failed attempt to rescue in jured neurons,although its up-regulation was previously considered an indication of apoptosis.These observations thus rekindle an old quest to identify new neuroprotective targets to minimize the stroke damage.In this review,the author will examine the evidence that indicates the participation of CDKs and p53 in DND and then introduce pre-clinical data to explore CDK inhibition as a potential neuroprotective target.Finally,using CDK inhibition as an example,this paper will discuss the pertinent criteria for a viable neuroprotective strategy for ischemic in jury.     

胸廓矢状面倾斜度的测定及其对放疗的意义

目的了解人体前胸矢状面倾斜度的大小及对放疗剂量分布的影响。方法选择126例患者行胸部CT扫描并予正中矢状面重建。分别测定上中下胸廓层面前后体表中线至脊髓距离及各层上下间距,计算出前胸倾斜度。查TMR表得出中平面深度及脊髓深度处上中胸及中下胸层面剂量误差。结果前野各层面至脊髓距离变化较大,后野变化较小。人体前胸倾斜度范围为25~56°。上中胸段组的上下缘剂量误差较大,躯体中平面平均相差8%,脊髓17%。中下胸段组剂量误差较小,躯体中平面4%,脊髓7%。误差随倾斜角度增加而增加。根据倾斜度得出合适的楔形板修正角度大约为10~35°。结论人体前胸矢状面存在自然倾斜度,这种倾斜影响前野剂量分布,应予以个体化修正。建议根据角度的大小选择合适的头足向楔形板优化。     

Sodium MRI of the human kidney at 3 Tesla.

The sodium concentration gradient in the kidney (from the cortex to the medulla) serves to regulate fluid homeostasis and is tightly coupled to renal function. It was previously shown that renal function and pathophysiology can be characterized in rat kidneys by measuring the sodium gradient with (23)Na MRI. This study demonstrates for the first time the ability of (23)Na MRI to map the distribution of sodium in the human kidney and to quantify the corticomedullary sodium gradient. The study was performed on a 3T Signa LX scanner (GE) using an in-house-built quadrature surface coil. (23)Na images of volunteers were acquired using a 3D coronal gradient-echo sequence at a spatial resolution of 0.3 x 0.3 x 1.5 cm(3) in a 25-min scan time. The signal intensity (relative to the noise) increased linearly from the cortex to each of the medullae with a mean slope of 1.6 +/- 0.2 in relative arbitrary units per mm (Rel.u./mm, N = 6) and then decreased, as expected, toward the renal pelvis. Water deprivation (12 hr) induced a significant increase of 25% (P < 0.05) in this gradient. Based on these results, we suggest that sodium MRI can serve as a valuable noninvasive method for functional imaging of the human kidney.     

CLINICAL OBSERVATION ON THERAPEUTIC EFFECTS OF COMBINED TREATMENT OF NONINSULIN DEPENDENT DIABETES

Thetherapeuticeffectofacupuncturefordia betesmellitus(DM)hasbeenconfirmedbyalarge numberofclinicalinvestigations.Itisasubjectfor acupuncturiststoconsiderandsearchforatherapy providingbettertherapeuticeffectsbywayofproper differentiationofsyndromesandcombinationofacu points.Basedonclinicalexperiencegainedformore than30years,theauthorsofthepresentpaperhave graduallyformedaneffectivecombinedtherapyfor treatingtypeⅡDM(noninsulindependentDM)and itsvariouscomplications.Thereportisasfollows.1CLI…