Patterns of Hepatitis C Virus RNA Levels during Acute Infection: The InC3 Study

Background

Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection.

Methods

Data were from an international collaboration of nine prospective cohorts of acute HCV (InC³ Study). Participants with well-characterized acute HCV infection (detected within three months post-infection and interval between the peak and subsequent HCV RNA levels≤120 days) were categorised by a priori-defined patterns of HCV RNA levels: i) spontaneous clearance, ii) partial viral control with persistence (≥1 log IU/mL decline in HCV RNA levels following peak) and iii) viral plateau with persistence (increase or <1 log IU/mL decline in HCV RNA levels following peak). Factors associated with HCV RNA patterns were assessed using multinomial logistic regression.

Results

Among 643 individuals with acute HCV, 162 with well-characterized acute HCV were identified: spontaneous clearance (32%), partial viral control with persistence (27%), and viral plateau with persistence (41%). HCV RNA levels reached a high viraemic phase within two months following infection, with higher levels in the spontaneous clearance and partial viral control groups, compared to the viral plateau group (median: 6.0, 6.2, 5.3 log IU/mL, respectively; P=0.018). In the two groups with persistence, Interferon lambda 3 (IFNL3) CC genotype was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95%CI: 1.08, 7.02). In the two groups with viral control, female sex was independently associated with spontaneous clearance compared to partial viral control (AOR: 2.86; 95%CI: 1.04, 7.83).

Conclusions

Among individuals with acute HCV, a spectrum of HCV RNA patterns is evident. IFNL3 CC genotype is associated with initial viral control, while female sex is associated with ultimate spontaneous clearance.     

Assessment of Radiation and Heavy Metals Risk due to the Dietary Intake of Marine Fishes (Rastrelliger kanagurta) from the Straits of Malacca

The environment of the Straits of Malacca receives pollution as a result of various industrial and anthropogenic sources, making systematic studies crucial in determining the prevailing water quality. Present study concerns concentrations of natural radionuclides and heavy metals in marine fish (Rastrelliger kanagurta) collected from the Straits of Malacca, since aquatic stock form an important source of the daily diet of the surrouding populace. Assessment was made of the concentrations of key indicator radionuclides (²²⁶Ra, ²³²Th, ⁴⁰K) and heavy metals (As, Mn, Fe, Cr, Ni, Zn, Cu, Co, Sr, Al, Hg and Pb) together with various radiation indices linked to the consumption of seafish. The annual effective dose for all detected radionuclides for all study locations has been found to be within UNSCEAR acceptable limits as has the associated life-time cancer risk. The overall contamination of the sampled fish from heavy metals was also found to be within limits of tolerance.     

Assessment of Natural Radioactivity Levels and Potential Radiological Risks of Common Building Materials Used in Bangladeshi Dwellings

The concentrations of primordial radionuclides (²²⁶Ra, ²³²Th and ⁴⁰K) in commonly used building materials (brick, cement and sand), the raw materials of cement and the by-products of coal-fired power plants (fly ash) collected from various manufacturers and suppliers in Bangladesh were determined via gamma-ray spectrometry using an HPGe detector. The results showed that the mean concentrations of ²²⁶Ra, ²³²Th and ⁴⁰K in all studied samples slightly exceeded the typical world average values of 50 Bq kg⁻¹, 50 Bq kg⁻¹ and 500 Bq kg⁻¹, respectively. The activity concentrations (especially ²²⁶Ra) of fly-ash-containing cement in this study were found to be higher than those of fly-ash-free cement. To evaluate the potential radiological risk to individuals associated with these building materials, various radiological hazard indicators were calculated. The radium equivalent activity values for all samples were found to be lower than the recommended limit for building materials of 370 Bq kg^-1, with the exception of the fly ash. For most samples, the values of the alpha index and the radiological hazard (external and internal) indices were found to be within the safe limit of 1. The mean indoor absorbed dose rate was observed to be higher than the population-weighted world average of 84 nGy h^–1, and the corresponding annual effective dose for most samples fell below the recommended upper dose limit of 1 mSv y^–1. For all investigated materials, the values of the gamma index were found to be greater than 0.5 but less than 1, indicating that the gamma dose contribution from the studied building materials exceeds the exemption dose criterion of 0.3 mSv y^-1 but complies with the upper dose principle of 1 mSv y⁻¹.     

Developmental Exposure to Estrogen Alters Differentiation and Epigenetic Programming in a Human Fetal Prostate Xenograft Model

Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM) isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure.     

Promotion of Bone Morphogenetic Protein Signaling by Tetraspanins and Glycosphingolipids

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily of secreted molecules. BMPs play essential roles in multiple developmental and homeostatic processes in metazoans. Malfunction of the BMP pathway can cause a variety of diseases in humans, including cancer, skeletal disorders and cardiovascular diseases. Identification of factors that ensure proper spatiotemporal control of BMP signaling is critical for understanding how this pathway is regulated. We have used a unique and sensitive genetic screen to identify the plasma membrane-localized tetraspanin TSP-21 as a key new factor in the C. elegans BMP-like “Sma/Mab” signaling pathway that controls body size and postembryonic M lineage development. We showed that TSP-21 acts in the signal-receiving cells and genetically functions at the ligand-receptor level. We further showed that TSP-21 can associate with itself and with two additional tetraspanins, TSP-12 and TSP-14, which also promote Sma/Mab signaling. TSP-12 and TSP-14 can also associate with SMA-6, the type I receptor of the Sma/Mab pathway. Finally, we found that glycosphingolipids, major components of the tetraspanin-enriched microdomains, are required for Sma/Mab signaling. Our findings suggest that the tetraspanin-enriched membrane microdomains are important for proper BMP signaling. As tetraspanins have emerged as diagnostic and prognostic markers for tumor progression, and TSP-21, TSP-12 and TSP-14 are all conserved in humans, we speculate that abnormal BMP signaling due to altered expression or function of certain tetraspanins may be a contributing factor to cancer development.     

Differences in Field Effectiveness and Adoption between a Novel Automated Chlorination System and Household Manual Chlorination of Drinking Water in Dhaka,Bangladesh: A Randomized Controlled Trial

The number of people served by networked systems that supply intermittent and contaminated drinking water is increasing. In these settings, centralized water treatment is ineffective, while household-level water treatment technologies have not been brought to scale. This study compares a novel low-cost technology designed to passively (automatically) dispense chlorine at shared handpumps with a household-level intervention providing water disinfection tablets (Aquatab), safe water storage containers, and behavior promotion. Twenty compounds were enrolled in Dhaka, Bangladesh, and randomly assigned to one of three groups: passive chlorinator, Aquatabs, or control. Over a 10-month intervention period, the mean percentage of households whose stored drinking water had detectable total chlorine was 75% in compounds with access to the passive chlorinator, 72% in compounds receiving Aquatabs, and 6% in control compounds. Both interventions also significantly improved microbial water quality. Aquatabs usage fell by 50% after behavioral promotion visits concluded, suggesting intensive promotion is necessary for sustained uptake. The study findings suggest high potential for an automated decentralized water treatment system to increase consistent access to clean water in low-income urban communities.     

Selective toxic effects of polyunsaturated fatty acids derived from Ulva fasciata on red tide phyotoplankter species

Alpha-linolenic acid and linoleic acid isolated from Ulva fasciata showed toxic effects on red tide phytoplankters in a concentration-dependent manner. Among six species tested, raphidophycean flagellate Heterosigma akashiwo was the most susceptible to these fatty acids, and 50% lethal concentrations (LC50) of alpha-linolenic acid and linoleic acid were estimated to be 0.58 and 1.91 microg/ml respectively, whereas dinoflagellate Gymnodinium impudicum and Heterocapsa circularisquama were highly resistant and no significant toxic effects were observed up to 1,000 microg/ml. Both fatty acids were less toxic to fish (devil stinger), zooplankters (brine shrimp and rotifer), and mammalian cell lines (U937, HeLa, Vero, and CHO cells) than H. akashiwo.