Occult hepatitis B virus co-infection in human immunodeficiency virus-positive patients: A review of prevalence, diagnosis and clinical significance

The prevalence of human immunodeficiency virus(HIV) and hepatitis B virus(HBV) co-infection is high as they share similar mechanisms of transmission. The development and widespread use of highly sensitive tests for HBV diagnosis has demonstrated that a significant proportion of apparently healthy individuals with evidence of exposure to HBV continue to carry fully functional HBV DNA in their hepatocytes, a situation that predisposes them to the development of progressive liver disease and hepatocellular carcinoma. The presence of co-infections frequently influences the natural evolution of each of the participating infections present by either facilitating their virulence or competing for resources. Furthermore, the drugs used to treat these infections may also contribute to changes in the natural course of these infections, making the analysis of the impact of co-infection more difficult. The majority of studies has examined the impact of HIV on overt chronic hepatitis B, finding that co-infection carries an increased risk of progressive liver disease and the development of hepatocellular carcinoma. Although the effect of HIV on the natural history of occult hepatitis B infection(OBI) has not been fully assessed, all available data suggest a persisting risk of repeated flares of hepatitis and progressive liver disease. We describe studies regarding the diagnosis, prevalence and clinical significance of OBI in HIVpositive patients in this short review. Discrepancies in worldwide prevalence show the urgent need for the standardization of diagnostic criteria, as established by the Taormina statements. Ideally, standardized protocols for testing should be employed to enable the comparison of data from different groups. Additional studies are needed to define the differences in risk for OBI without HIV and in HIV-HBV co-infected patients with or without overt disease.

Are the mechanisms involved in astrocyte and lymphocyte death during HIV infection similar?

Acquired immune deficiency syndrome is associated with the death of CD4+ T lymphocytes. The entry of the human immunodeficiency virus (HIV) into the central nervous system leads to a broad spectrum of HIV-associated neurocognitive disorders (HAND) ranging from mild to severe dementia. Inside the central nervous system, HIV establishes infection in astrocytes - the predominant cell type in the brain, thus causing neuropathology, but the underlying mechanisms remain unknown.

Molecular Modeling of Potential Dual Inhibitors of HIV Reverse Transcriptase and Integrase

With the goal of suggesting dual inhibitors of HIV reverse transcriptase (RT) and integrase (IN), herein we report the molecular docking of an initial set of 556 compounds related to the pyridinone class. Docking with multiple crystallographic structures of HIV-1 RT led to 160 potential binders of RT interacting with key amino acid residues at the enzyme’s allosteric site. Compounds selected from the docking with RT were further docked with a crystallographic structure of HIV-1 IN. A total of 31 structures had the potential to make contacts with Mg2+ ions located in a small space between DNA and IN. Interactions with Mg2+ ions are relevant because they participate in the stabilization of the IN-DNA complex. In conclusion, 31 compounds synthetically accessible are proposed as dual inhibitors of RT and IN. It is hypothesized that the suggested compounds will inhibit RT by occupying the allosteric site for NNRTIs and will inhibit the catalytic activity of IN by destabilizing the IN-DNA complex. The main perspective of this work is the synthesis and biological testing of the candidate molecules.

Sensory neurons in the spinal cord of nominal female embryos in the marine turtle Lepidochelys olivacea respond to shifts in incubation temperature:implications for temperature dependent sex determination

Gonadal determination in marine turtles depends on incubation temperature. The mechanisms that spark off this process remain unclear. Previously, we proposed that sensory nerves reaching the gonadal primordium in nominal female embryos of Lepidochelys (L) olivacea may sense and signal incubation temperature. These nerves could later trigger ovarian determination by releasing neurotransmitters in a code constructed based on the thermal information (Gutierrez-Ospina et al., Acetylcholinesterase-positive innervation is present at the undifferentiated stages of the sea turtle Lepidochelys olivacea embryo gonads: implications for temperature-dependent sex determination, J. Comp. Neurol. 410 (1999) 90-98). The hypothesis briefly described, however, has been recently refuted under weak theoretical grounds and experimental misinterpretations (see introduction). Here, we present preliminary results that show that nominal female embryos have sensory neurons located in the dorsal horn laminae I and II of the lumbar spinal cord that display increased c-Fos-like immuno-staining after being incubated either at 15°C or 50°C. Because these spinal neurons are the primary central target of dorsal root ganglion neurons that innervate the urogential crest, these observations keep open the possibility that gonadal sensory nerves indeed signal thermal information that could later be used to trigger or instruct ovarian specification in marine turtles.

腺苷A_2型受体在肝窦内皮细胞一氧化氮生成中的作用

目的研究腺苷A2型受体在肝窦内皮细胞(HSECs)一氧化氮生成中的作用。方法分别将腺苷、腺苷A1型受体激动剂R鄄PIA和腺苷A2型受体激动剂CGS21680与原代培养的HSEC共培养20min、40min、60min后,用RT鄄PCR测定HSECeNOSmRNA的表达,并测定HSEC内一氧化氮(NO)含量的变化。结果与对照组相比,腺苷和CGS21680都能促使HSEC内eNOSmRNA表达增加,提高HSEC内NO含量(P<0.05),而R鄄PIA却无此作用(P>0.05)。结论HSEC通过腺苷A2型受体的兴奋作用产生大量NO。

Gene expression changes after hypoxic preconditioning in rat hepatocytes

BACKGROUND: Hypoxic preconditioning can protect hepatocytes against hypoxic injury, but its mechanism has not been elucidated. The aim of this study was to profile gene expression patterns involved in hypoxic preconditioning and probable mechanism at the level of gene expression. METHODS: Hepatocytes were divided into 2 groups: control group and hypoxic preconditioning group. Biotinlabeled cRNA from the control group and the hypoxic preconditioning group was hybridized by oligonucleotide microarray. Genes that were significantly associated with hypoxic preconditioning were filtered, and validated at the level of transcript expression. RESULTS: Forty-three genes with significantly altered expression patterns were discovered and most of them had not been previously reported. Among these genes,genes encoding superoxide dismutase 2 (SOD2)and interleukin 10 (IL-10) in the hypoxic preconditioning group were confirmed to be up-regulated with real-time quantitative PCR. CONCLUSIONS: Many cytokines are involved in hypoxic preconditioning and protect hepatocytes from hypoxiareoxygenation injury, and the increase of oxygen freeradical scavengers and anti-inflammatory factors may play a key role in this phenomenon. Diverse signal pathways are probably involved.

Hematotesticular barrier is altered from early stages of liver cirrhosis:Effect of insulin-like growth factor 1

AIM: The pathogenesis of hypogonadism in liver cirrhosis is not well understood. Previous results from our laboratory showed that IGF-1 deficiency might play a pathogenetic role in hypogonadism of cirrhosis. The administration of IGF-1 for a short period of time reverted the testicular atrophy associated with advanced experimental cirrhosis.The aim of this study was to establish the historical progression of the described alterations in the testes,explore testicular morphology, histopathology, cellular proliferation, integrity of testicular barrier and hypophysogonadal axis in rats with no ascitic cirrhosis.METHODS: Male Wistar rats with histologically-proven cirrhosis induced with carbon tetrachloride (CC14) for 11 wk,were allocated into two groups (n = 12, each) to receive recombinant IGF-1 (2 μg/100 g·d, sc) for two weeks or vehicle. Healthy rats receiving vehicle were used as control group (n = 12).RESULTS: Compared to controls, rats with compensated cirrhosis showed a normal testicular size and weight and very few histopathological testicular abnormalities.However, these animals showed a significant diminution of cellular proliferation and a reduction of testicular transferrin expression. In addition, pituitary-gonadal axis was altered, with significant higher levels of FSH (P<0.001 vs controls) and increased levels of LH in untreated cirrhotic animals. Interestingly, IGF-1 treatment normalized testicular transferrin expression and cellular proliferation and reduced serum levels of LH (P = ns vs controls, and P<O.01 vs untreated cirrhotic group).CONCLUSION: The testicular barrier is altered from an early stage of cirrhosis, shown by a reduction of transferrin expression in Sertoli cells, a diminished cellular proliferation and an altered gonadal axis. The treatment with IGF-1 could be also useful in this initial stage of testicular disorder associated with compensated cirrhosis.

Hepatitis C virus treatment failure:Clinical utility for testing resistance-associated substitutions

The hepatitis C virus has a high mutation capacity that leads to the emergence of resistance-associated substitutions(RAS).However,the consequence of resistance selection during new direct-acting antiviral drug(DAA)treatment is not necessarily the therapeutic failure.In fact,DAA treatment has shown a high rate(>95%)of sustained virological response even when high baseline RAS prevalence has been reported.In the context of RAS emergence and high rates of sustained viral response,the clinical relevance of variants harboring RAS is still controversial.Therefore,in order to summarize the data available in international guidelines,we have reviewed the clinical utility of testing RAS in the era of new pangenotypic DAA drugs.

Cytogenetic and Molecular Characterization of Hematological Neoplasm in an Ecuadorian Population

Cancer is one of the major causes of mortality in Ecuador and annually, hematological malignancies are within the top ten most common cancers. In this multicentric study, we analyzed a series of patients diagnosed with different hematological disorders between the years 1984 and 2012. Chromosome abnormalities were detected in 1886 (45.9%) patients. FISH and RT-PCR techniques were used in order to determine the presence of genetic rearrangements and complement conventional cytogenetics results. Using FISH and RT-PCR, positive cases were increased by 1.8% and 6.9% respec- tively. We analyzed fusion genes resulting from t(8;21), t(15;17), inv(16), t(9;22), 11q23 rearrangements, t(4;11) and t(1;19). The frequency of transcripts of some of these fusion genes was of particular interest as our results differ from studies on other populations. Specifically, the fusion gene BCR-ABL was present in the form of the b2/a2 transcript in 95% of CML patients and in the form of b3/a2 transcript in the remaining 5%. The PML-RARA fusion gene also showed a distinct pattern of transcript expression. This fusion gene exhibited the bcr2 (36%) and bcr3 (64%) transcripts, how- ever the bcr1 transcript was absent from our sample population. All cases carrying the CBFB-MYH11 fusion gene ex- hibited the F transcript. This was also of interest due to the rarity of this particular transcript worldwide. Finally all cases carrying the MLL-AF4 fusion gene displayed the e7-e8 transcript. The frequency of the subtypes of some fusion genes differ from those reported in other populations, possibly due to the particular genetic make-up of the Ecuadorian population, mostly mestizo, as well as environmental factors.

Differential effect of biotin on carboxylase activity and mice skeletal muscle metabolism

In mammalian skeletal muscle there are four carboxylases involved in several biochemical processes like gluconeogenesis, tricarboxylic acid cycle anaplerosis, metabolism of fatty acids and metabolism of various amino acids. It has been shown that biotin deficiency reduces body weight at the expense of muscular mass. When necessary, the liver uses skeletal muscle protein to provide glucose and amino acids to organs in need of such compounds. In this paper we analyzed carboxylase specific activities in hind limb skeletal muscle of 3 weeks old BALB/c male mice, at 0, 1, 4, 7, and 14 days of a specific diet with different biotin concentrations. Biotin was used at 0.0, 1.8 or 98.2 mg per kg of food;and was referred to as biotin deficient, sufficient and supplemented, respectively. Water and food supply and consumption by the three groups of mice were the same. Therefore, the observed effects were directly related to biotin ingestion. The body weight of biotin supplemented mice was the same as the body weight of mice in the biotin sufficient group, while biotin deficiency caused body weight reduction after 7 days of biotin depletion. We found that the total protein concentration in the vastus lateralis muscle is associated with the biotin content in the diet. After 7 days, the muscle total protein content was lower in mice of the biotin deficient group while it was higher in the mice from the biotin supplemented group

Marine turtle hatchlings use multiple sensory cues to orient their crawling towards the sea:biological and conservation policy implications

The ability of sea turtle hatchlings to find the seashore soon after hatching is thought to be exclusively dependent upon visual information. Target-oriented movements in most vertebrates, however, relay on combining information gathered through different sensory systems. Hence, in this work, we investigated whether olfactory and/or magnetic information might complement visual cues during hatchling’s seaward crawling. Acute olfactory deprivation and distorted magnetic sensation in visually competent hatchlings resulted in a scattering of seaward crawling routes among cardinal points, some of them being different from those strongly preferred by control hatchlings. In addition, blindfolded hatchlings also displayed a striking misrouting while crawling on the beach surface in spite of having intact olfactory and magnetic senses. Together these results support the notion that visual information is crucial for seaward crawling, but also that olfactory and magnetic information complement visual cues when turtle hatchlings display this behavior. Hence, the present observations suggest that multisensory cues are used by turtle hatchlings while crawling towards the sea. This work also has important implications on the design of species conservation measures and policies. In the near future, efforts must be made to identify and preserve the local natural sources of odors and magnetic cues, in addition to preventing the perturbing effects of artificial lighting on adult and hatchling turtle crawling behavior.

Increased serotonin concentration and tryptophan hydroxylase activity in reproductive organs of copulator males:a case of adaptive plasticity

Individual male rats may systematically display or not copulatory behavior when paired with receptive females. Although these phenotypes are associated with differences in brain organization and function, they might also do so at the level of the reproductive organs. We then used high performance liquid chromatography to quantify serotonin concentration and the activity of tryptophan hydroxylase in the reproductive organs of copulator and non-copulator males. Sexual behavior display was compared between groups and parameters of fertility and reproductive fitness were determined for copulator males. Copulator males had higher concentrations of serotonin in the epididymis, testicle and ventral prostate than their non-copulator counterparts, as it was found for epididymal and testicular tryptophan hydroxylase activity. However, preliminary data shows that serotonin elevation occurs in copulator males only until they have accumulated several sexual encounters, so it might be a response to genital gratification or sexual rewarding. Interestingly, only epididymal serotonin concentration correlated with reproductive fitness, offspring number, mating success and seminal plug volume in copulator males. Our results support that copulator and non-copulator male rats feature a phenotype-specific serotoninergic tone in the epididymis, testicle and ventral prostate gland. The observation documenting that epididymal serotonin concentration correlated with parameters that monitor male fertility and reproductive fitness in copulator males predicts that epididymal factors increase their chances of parenting offspring.

Cortical columns(barrels)display normal size in the brain’s primary somatosensory cortex of mice carrying null mutations of the insulin receptor substrate 1 gene:A preliminary report

Circuits in barrels of the rodent brain’s primary somatosensory (S1) cortex build up following constructivist rules. Previous evidence in mice supports that the precise addition of barrel neuropil is promoted by insulin-like growth factor-1 (IGF-1). The signaling cascades mediating this response remain undetermined. To address whether the effects of IGF-1 upon the growth of S1 circuits are mediated by insulin receptor substrate-1 (IRS-1), we studied barrel size in adult mice having the IRS-1 gene knocked out (IRS-1 ko). Our results reveal that barrel size is similar between wild type and IRS-1 ko mice suggesting that IRS-1 is not essential for barrel circuitry growth. Hence, investigations aimed at exploring other substrates activated by IGF-1, namely IRS-2 and IRS-4, are needed to reveal signaling pathways that mediate the precise addition of S1 neuronal circuitry.

Studying Some Brain and Ovarian Morphological Traits in Diaglena spatulata Female Frogs Thriving in Conserved and Perturbed Habitats:A Preliminary Report and Its Implications for Amphibian Survival and Continuity

Amphibians are thought to be highly susceptible to perturbed environments. However, recent studies show that many of them are successful inhabitants of disturbed, fragmented habitats. The source of this resilience is yet unclear, but it may be the byproduct of having a robust phenotype and/or the result of phenotypic plasticity. We then assessed the contribution of each by evaluating cytological features of two brain nuclei that modulate reproductive behavior and of the ovary, using female specimens of the frog Diaglena spatulata prospering in conserved and disturbed areas of a tropical dry forest. Our results in the brain show that the medial amygdala, but not the preoptic area, had a reduced size in frogs collected in disturbed forests compared to specimens collected in conserved forests. Both brain nuclei displayed, however, neurons with a reduced size in frogs captured in disturbed forest patches. In contrast, ovarian cytological features were similar between groups. Our preliminary results lead us to propose that Diaglena spatulata female specimens might combine robust ovary and plastic brain’s phenotypic traits to confront disturbed environments. This, however, is still a working hypothetical framework that needs to be experimentally confirmed.

Glycosylation on proteins of the intestine and perimicrovillar membrane of Triatoma (Meccus) pallidipennis, under different feeding conditions

Trypanosoma cruzi,the causative agent of Chagas disease, interacts with molecules in the midgut of its insect vector to multiply and reach the infective stage. Many studies suggest that the parasite binds to midgut-specific glycans. We identified several glycoproteins expressed in the intestine and perimicrovillar membrane (PMM) of Triatoma (Meccus) pallidipennis under different feeding conditions. In order to assess changes in protein-linked glycans, we performed lectin and immunoblot analyses on glycoprotein extracts from these intestinal tissues using well-characterized lectins, and an antibody, which collectively recognize a wide range of different glycans epitopes. We observed that the amount and composition of proteins and glycoproteins associated with different glycans structures changed over time in the intestines and PMM under different physiological conditions. PMM extracts contained a wide variety of glycoproteins with different sugar residues, including abundant high-mannose and complex sialylated glycans. We propose that these molecules could be involved in the process of parasite-vector interactions.

肝窦内皮细胞一种新的分离和培养方法

本文在利用Percoll梯度密度离心法纯化肝窦内皮细胞（hepatic sinus endothelial cell,HSEC）的基础上,建立一种新的HSEC分离和培养方法,以提高HSEC的得率、活力和体外培养时间.

Transcriptional cofactors Ski and SnoN are major regulatorsof the TGF-β/Smad signaling pathway in health and disease

The transforming growth factor-β(TGF-β)family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis.The TGF-βsignaling pathway outcome relies on the control of the spatial and temporal expression of>500 genes,which depend on the functions of the Smad protein along with those of diverse modulators of this signaling pathway,such as transcriptional factors and cofactors.Ski(Sloan-Kettering Institute)and SnoN(Ski novel)are Smadinteracting proteins that negatively regulate the TGF-βsignaling pathway by disrupting the formation of R-Smad/Smad4 complexes,as well as by inhibiting Smad association with the p300/CBP coactivators.The Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone deacetylases to repress gene transcription.The TGF-β/Smad pathway and coregulators Ski and SnoN clearly regulate each other through several positive and negative feedback mechanisms.Thus,these cross-regulatory processes finely modify the TGF-βsignaling outcome as they control the magnitude and duration of the TGF-βsignals.As a result,any alteration in these regulatory mechanisms may lead to disease development.Therefore,the design of targeted therapies to exert tight control of the levels of negative modulators of the TGF-βpathway,such as Ski and SnoN,is critical to restore cell homeostasis under the specific pathological conditions in which these cofactors are deregulated,such as fibrosis and cancer.

Skeletal muscle myogenesis is regulated by G protein-coupled receptor kinase 2

G 联合蛋白质的受体 kinase (GRK2 ) 2 是调整不同的膜 receptorsand 的重要 serine/threonine-kinase 细胞内部的蛋白质。在胚胎或成年苍蝇的果蝇 Gprk2 的变细导致了体的肌肉，纤维的损失，和不能飞行的 phenotype.In 的有缺点的区别脊椎动物， GRK2 hemizygous 老鼠少些，但是更包含了 hypertrophied 骨胳的肌肉纤维比野类型的 littermates.In C2C12 myoblasts ， GRK2 kinase缺乏的异种( K220R )的 overexpression 引起了房间 intoimmature myotubes 的早熟的区别，它在尺寸是更宽的并且包含了更多的熔化原子核，当时 GRK2 overexpression b 熔化事件由提高的 GRK2 层次支持了的损害 differentiationand 少数被 p38MAPK 异种概括，它能由 GRK2 模仿 p38MAPK 的 theinhibitory phosphorylation，而在表示 GRK2 观察的弄钝的区别面对 p38MAPK 小径的一个组成地活跃的在上游的激发器克隆 wasrescued。这些结果建议 thatbalanced GRK2 功能为一个及时、完全的 myogenic 过程是必要的。

Ethnobotanical survey of medicinal plants used in the management of cancer and diabetes

OBJECTIVE:To conduct an ethnobotanical survey and document the traditional anticancer and antidiabetic plants used by the local tribes of Mizoram,Northeast India.METHODS:A systematic survey was conducted in rural and urban areas of Mizoram by interviewing traditional practitioners,and cancer and diabetes patients.A detailed literature search was carried out using MEDLINE and SCOPUS and available literatures were selected and included in the study.The use value(UV)of the selected plants was calculated based on the number of citations per species given by informants.RESULTS:Data was obtained for 201 traditional medicinal plants from Mizoram,Northeast India.These plants were from 72 different families and belonged to 140 genera.Of these,103 plants were reported for the first time as possessing either anticancer or antidiabetic potential,and 105 plants were identified that were used for the treatment of both diseases.Three plants(Phlogacanthus thysiformis,Solanum gilo and Lobelia angulata)with antidiabetic potential,and six plants(Dillenia scabrella,Circium sinesis,Eupatorium nodiflorum,Pratia begonifolia,Vernonia teres and Plantago erosa)with both as anticancer and antidiabetic potential were documented for the first time.CONCLUSION:In this study,we documented several explored and unexplored medicinal plants that may be useful for the management of cancer and diabetes.This study suggests that there is a broad scope fordeveloping potent anticancer and antidiabetic agent from the flora of Mizoram,Northeast India.