A single nucleotide polymorphism in IL28B affects viral evolution of hepatitis C quasispecies after pegylated interferon and ribavirin therapy

Interleukin‐28B (IL28B) polymorphisms are associated with viral response to peginterferon and ribavirin (RBV) in chronic hepatitis C (HCV). Their recognition represents a breakthrough in the understanding of the role of the host in viral eradication. How these polymorphisms determine viral eradication is unknown. The IL‐28B variants are hypothesized to have a differential impact on HCV quasispecies evolution during treatment with pegylated interferon (PEG‐IFN) and RBV. In this study, HCV RNA levels were measured at early time points in 33 naïve genotype 1 hepatitis C patients and clonal analysis of the entire NS5A region was performed on sera from baseline and Day 7. Site rs12979860 polymorphisms were determined by direct sequencing of PCR products and classified into CC, CT, and TT and were identified in 13, 11, and 9 patients, respectively. The CC polymorphism more commonly was seen in Whites versus Blacks [12/21 (57%) vs. 1/12 (8%), P = 0.009] and HIV‐infected versus mono‐infected [13/25 (52%) vs. 0/8 (0%), P = 0.009]. Patients with CC and non‐CC had similar baseline viral loads. More patients with the CC polymorphism had amino acid substitutions in NS5A compared to non‐CC patients. Despite similar baseline viral diversity, by Day 7, significantly more patients with CC had higher non‐synonymous substitution values compared to non‐CC (P = 0.02). Chronic hepatitis C patients with the CC IL28B polymorphism have a higher number of amino acid substitutions in the NS5A region and early viral evolution due to greater interferon induced selective pressure during this critical period of treatment. J. Med. Virol. 84:1913–1919, 2012. © 2012 Wiley Periodicals, Inc.     

Advances in the diagnosis and treatment of tuberculosis

Although truly major advances that would revolutionize tuberculosis (TB) diagnosis and treatment have not been realized, we are beginning to see the innovations that have been prompted by the recognition of the economic potential of the market for new diagnostic tests and treatments for TB and considerably increased public and private funding. Despite the enormous global burden of TB and the overall low rates of case detection worldwide, conventional approaches to diagnosis have, until recently, relied on tests that have major limitations. In this review of advances in diagnosis, we focus on strengths and limitations of newer tests that are available for the diagnosis of latent and active tuberculosis and rapid detection of drug resistance, specifically, tests that measure release of IFN-gamma in response to stimulation by Mycobacterium tuberculosis antigens, nucleic acid amplification for identification of M. tuberculosis complex, and rapid tests for detecting drug resistance. Standard regimens for treating TB have not changed for more than 30 yr and still require a minimum of 6 mo to have a high likelihood of a lasting cure. In this article, we focus on important changes in the philosophy of treatment, emphasizing the responsibility of the provider to assure successful completion of treatment, and on the roles of existing anti-TB agents and newer drugs such as rifabutin, rifapentine, and fluoroquinolones.     

Prevention of tuberculosis in HIV-infected patients

PURPOSE OF REVIEW: The pandemic of HIV infection has contributed to a significant increase in tuberculosis rates worldwide. Tuberculosis is one of the most common opportunistic infections in HIV-infected patients, and the leading cause of death. In order to control tuberculosis in areas with high rates of co-infection, strategies must be developed to prevent tuberculosis in HIV-infected individuals. RECENT FINDINGS: Recent reviews have highlighted the burden of HIV-related tuberculosis in the world and the necessary steps that must be taken to control tuberculosis in certain high-risk regions like sub-Saharan Africa. The Centers for Disease Control and Prevention has recently published guidelines for the use of the diagnostic test QuantiFERON-TB Gold, and cautioned about interpretation of this test in HIV-infected patients because of a lack of information regarding performance in these individuals. Perhaps the most significant studies over the past year have reported the impact that treating HIV infection can have on the risk of tuberculosis. SUMMARY: HIV and tuberculosis continue to be linked in a global pandemic. In addition to the standard approaches to tuberculosis control, such as the diagnosis and treatment of tuberculosis and latent tuberculosis infection, recent studies have demonstrated that treatment of HIV itself may also have a role in tuberculosis control.     

Percutaneous Gastric Drainage as a Treatment for Small Bowel Obstruction after Gastric Bypass

The authors report the case of a patient who developed small bowel obstruction after laparoscopic gastric bypass. Imaging revealed an obstruction at the enteroenterostomy resulting in dilation of the bypassed stomach and proximal small bowel. The bypassed stomach was percutaneously drained using CT guidance, leading to resolution of the small bowel obstruction. Biliopancreatic limb obstructions can be successfully treated non-operatively after gastric bypass.     

Endovascular abdominal aortic stenosis treatment with the optimed self‐expandable nitinol stent

Purpose: To evaluate the safety and feasibility of self‐expandable stents (OptiMed) for treatment of abdominal aortic stenosis in the situations in which the aortic stenosis locates near the origin of celiac, superior mesenteric, renal and inferior mesenteric arteries. Methods: Five consecutive patients scheduled for endovascular treatment of abdominal aortic stenosis by self‐expandable nitinol stent (Sinus‐Aorta/OptiMed) implantation. The diameter of the stent was chosen as 10–30% more than that of the normal portion of the aorta above the stenosis. Long stents of 60 mm or longer were chosen. After stent deployment, balloon postdilation was performed with a balloon in patients with residual gradient > 5 mm Hg. Results: All patients were successfully treated with the OptiMed stents. The balloon predilation was performed in one patient due to severe stenosis. The mean diameter and length of the stents deployed were 20.4 ± 2.9 (range, 16–24 mm) and 64 ± 8.9 (range, 60–80 mm), respectively. The balloon postdilation was performed in all cases. The mean diameter of the balloons was 13.6 ± 1.5 (range, 12–15 mm). The mean diameter of stenosis increased from 4.8 ± 1.9 to 14.4 ± 1.8 mm after stent placement. The mean peak systolic gradient decreased from 46.8 ± 31.5 mm Hg to 0.8 ± 1.8 mm Hg. During follow‐up (22.8 ± 14.3 months), none of the patients had restenosis within the stent, occlusion of any branches of the aorta, or other related complications. Conclusions: In our small series, we observed that abdominal aortic stenosis can be successfully and effectively treated with OptiMed stents in the situations in which the stenotic segment is located next to the origins of the main visceral branches of abdominal aorta. © 2009 Wiley‐Liss, Inc.     

Preparation and characterization of ketoprofen-loaded solid lipid nanoparticles made from beeswax and carnauba wax

Solid lipid nanoparticles (SLNs) have been proposed as suitable colloidal carriers for delivery of drugs with limited solubility. Ketoprofen as a model drug was incorporated into SLNs prepared from a mixture of beeswax and carnauba wax using Tween 80 and egg lecithin as emulsifiers. The characteristics of the SLNs with various lipid and surfactant composition were investigated. The mean particle size of drug-loaded SLNs decreased upon mixing with Tween 80 and egg lecithin as well as upon increasing total surfactant concentration. SLNs of 75 ± 4 nm with a polydispersity index of 0.2 ± 0.02 were obtained using 1% (vol/vol) mixed surfactant at a ratio of 60:40 Tween 80 to egg lecithin. The zeta potential of these SLNs varied in the range of –15 to –17 (mV), suggesting the presence of similar interface properties. High drug entrapment efficiency of 97% revealed the ability of SLNs to incorporate a poorly water-soluble drug such as ketoprofen. Differential scanning calorimetry thermograms and high-performance liquid chromatographic analysis indicated the stability of nanoparticles with negligible drug leakage after 45 days of storage. It was also found that nanoparticles with more beeswax content in their core exhibited faster drug release as compared with those containing more carnauba wax in their structure.From the Clinical EditorKetoprofen as model drug was incorporated into solid lipid nanoparticles, which have been proposed as suitable colloidal carriers for delivery of drugs with limited solubility. High drug entrapment efficiency, stability of nanoparticles with negligible drug leakage and fast drug release can be accomplished using this technology.     

Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion

Having identified renin in cardiac mast cells, we assessed whether its release leads to cardiac dysfunction. In Langendorff-perfused guinea pig hearts, mast cell degranulation with compound 48/80 released Ang I-forming activity. This activity was blocked by the selective renin inhibitor BILA2157, indicating that renin was responsible for Ang I formation. Local generation of cardiac Ang II from mast cell-derived renin also elicited norepinephrine release from isolated sympathetic nerve terminals. This action was mediated by Ang II-type 1 (AT1) receptors. In 2 models of ischemia/reperfusion using Langendorff-perfused guinea pig and mouse hearts, a significant coronary spillover of renin and norepinephrine was observed. In both models, this was accompanied by ventricular fibrillation. Mast cell stabilization with cromolyn or lodoxamide markedly reduced active renin overflow and attenuated both norepinephrine release and arrhythmias. Similar cardioprotection was observed in guinea pig hearts treated with BILA2157 or the AT1 receptor antagonist EXP3174. Renin overflow and arrhythmias in ischemia/reperfusion were much less prominent in hearts of mast cell-deficient mice than in control hearts. Thus, mast cell-derived renin is pivotal for activating a cardiac renin-angiotensin system leading to excessive norepinephrine release in ischemia/reperfusion. Mast cell-derived renin may be a useful therapeutic target for hyperadrenergic dysfunctions, such as arrhythmias, sudden cardiac death, myocardial ischemia, and congestive heart failure.     

Thermosensitive Drug Permeation through Liquid Crystal-Embedded Cellulose Nitrate Membranes

In this study, the application of thermotropic liquid crystals embedded in cellulose nitrate membranes as on-off drug permeation control in response to temperature changes is described. Two low-molecular-weight liquid crystals, n-pentyl-cyanobiphenyl (K15) and n-heptyl-cyanobiphenyl (K21), with nematic-to-isotropic phase transition temperatures (T(n-i)) of 36.3 °C and 43.3 °C, respectively, were used to modulate drug permeation through the membrane. Liquid crystal-embedded membranes composed of appropriate blends of K15 and K21 were prepared by vacuum filtration. The permeation of pyrazinamide and metronidazole as drug models with different hydrophilicity and molecular weights through the liquid crystal-embedded membrane was examined. It was found that the drug permeation through the membrane could be modulated by changing the temperature below and above the T(n-i) of liquid crystals. The permeation of pyrazinamide, the hydrophilic drug with smaller molecular weight, was more temperature-dependent than metronidazole, the hydrophobic drug with higher molecular weight. These experiments were also repeated with thermal cycling between 25 °C and 45 °C. The permeation profiles were reversible and followed zero-order kinetics.     

Thermoresponsive Drug Delivery Using Liquid Crystal-Embedded Cellulose Nitrate Membranes

The aim of this study was to investigate the use of thermotropic liquid crystalline (TLC) blends of 4-pentyl-4′-cyanobiphenyl (K15) and 4-heptyl-4′-cyanobiphenyl (K21) with appropriate nematic to isotropic phase temperature (T_{n ? i}) just above body temperature as a temperature-modulated drug permeation system. Using differential scanning calorimetry (DSC) we showed that the phase transition temperature (T_{n ? i}) of K15 and K21 were 34.2°C and 41.5°C respectively. However, the thermogram of K15 and K21 blends with different ratios was shown to be a single endothermic peak similar to that of pure TLCs. K15 and K21 blends did not behave as a physical blend of two thermotropic liquid crystals with different T_{n ? i}. However, they are rather mixed together in such ways that behave like a single unit TLC. The T_{n ? i} of these TLC mixtures was linearly proportionate to the ratio of K15:K21. Using appropriate ratio of K15:K21 TLC, a mixture with desirable phase transition temperature was obtained. A triple layer of cellulose nitrate membranes containing a 50:50 mixture of K15 and K21 was used for drug permeation studies. This composite membrane showed good pulsatile permeation of drug molecules in response to temperature changes below and above the T_{n ? i} of the K15 and K21 blends in a reproducible and reversible manner. Paracetamol and methimazole were chosen as hydrophobic and hydrophilic drug models, respectively. Methimazole permeability through the TLC membrane was much higher (36.0 × 10^?5 cm/s) at temperatures above the phase transition temperature of liquid crystal blends than that (7.2 × 10^?5 cm/s) at temperatures below the phase transition temperature of liquid crystal blends (38.1°C).     

Hepatitis C and renal transplantation: a review on historical aspects and current issues

Chronic liver disease has a significant impact on the survival of renal transplant recipients with an incidence rate of 4-38%. Approximately, 8-28% of renal transplant recipients die due to chronic liver disease. Hepatitis C seems to be the leading cause of chronic liver disease in kidney recipients. Hepatitis C virus (HCV) infection has a wide range of prevalence (2.6-66%) among renal transplant recipients living in different countries with great genotype diversity in different parts of the world. Nowadays, antiviral drugs are used for the management of hepatitis C. Because of graft-threatening effects of some antiviral drugs used in HCV-infected renal transplant recipients, we specifically focused on HCV treatment after renal transplantation. Treatment of post-renal transplantation chronic liver disease with INF and ribavirin remains controversial. Anecdotal reports on post-renal transplantation hepatitis C demonstrate encouraging findings. This review summarises the most current information on diagnosis, treatment, prognosis, complications as well as the new aspects of treatment in HCV-infected renal transplant recipients. HCV belongs to the family of Flaviviridae, genus Hepacivirus.