61 Blood flow to the uterus and from the fetus is predominantly routed to the placentomes, which provides hematrophic nutrition from the mother to the fetus. Other functions of BNC and multinucleated syncytia Midostaurin datasheet include production and synthesis of proteins and hormones, like

placental lactogen, pregnancy-associated glycoproteins, and progesterone, that are involved in the growth of uterus and mammary gland and other maternal functions.59 In sheep, enJSRVs are abundantly expressed in the epithelia lining the different tissues of the female reproductive tract (vagina, cervix, uterus, and oviduct).62,63 In the uterus, both RNA and protein of enJSRVs are detected specifically in the endometrial LE and in the glandular epithelia.63–65 In addition, enJSRVs are expressed in the trophectoderm cells of the placenta in a temporal fashion that is coincident with key events in conceptus elongation and onset of trophoblast giant BNC differentiation.62 Within the placenta, enJSRVs are most abundant in the trophoblast giant BNC and multinucleated plaques of syncytiotrophoblast

3-MA in vitro within the placentomes throughout pregnancy. The RNA of enJSRVs is first detected in the conceptus on day 12.62 Interestingly, hyaluronoglucosaminidase 2 (HYAL2), a cellular receptor for both JSRV and enJSRVs Env,6,44 is detected exclusively in the BNC and the multinucleated syncytial plaques of the placenta.62 These observations led to the hypothesis that enJSRVs and HYAL2 are important for placental growth and differentiation in sheep.57 Indeed, injection of morpholinos that inhibit enJSRV Env production into the uteri of pregnant sheep on day 8 of pregnancy compromised conceptus elongation, resulting in reduced mononuclear trophoblast cell outgrowth and loss of trophoblast giant BNC differentiation.66

The biological role of HYAL2 in sheep conceptus development and differentiation has not been determined. Fig. 3 presents a current hypothesis on the biological roles of enJSRVs Env and HYAL2 in Tolmetin trophoblast development and differentiation in the sheep conceptus during early pregnancy. Interestingly, the enJSRVs Env have a high degree of similarity with the oncogenic exogenous JSRV Env; thus, it is tempting to speculate that both endogenous and exogenous JSRV Env share similar mechanisms to induce trophoblast proliferation/differentiation and cell transformation, respectively, because placental morphogenesis has features similar to tumorigenesis and metastasis.67,68 Although many of these parallels come from comparisons made with the human placenta, trophoblast cells in general have a high proliferation rate, are migratory and invasive, and have the capacity to evade the immune system, which are also characteristics of cancer cells.

SV2A, B and C RNA quantification was performed with the branched DNA-based QuantiGene 2.0 assay Kit (Panomics, Inc.) [24, 25] following the manufacturer’s procedure. The specific probe sets for SV2A, B and C were designed and supplied from Panomics. Gene expression was normalized to the housekeeping gene GAPDH. For the selection of the best housekeeping gene, five references (HPRT1, GUSB, GAPDH, PPIB and SDHA) were tested on four controls and 10 samples from epileptic patients. The coefficients of variability across samples were calculated. Based on this, the best one was SDHA with GAPDH close behind. For some samples, the signals obtained for SDHA were mTOR inhibitor too close to the background and

given that the quantity of the samples was limited, rather than use more Palbociclib supplier sample volume, GAPDH was chosen as reference. In all cases, consecutive sections (5 μm) from formalin-fixed paraffin embedded tissue were stained with commercial antibodies against NeuN, synaptophysin, SV2A, SV2B, SV2C, ZnT3 and

dynorphin. Briefly, sections were deparaffinated in xylene and rehydrated through graded alcohols (100%, 80%, 60%). Endogenous peroxidase was blocked by 0.3% hydrogen peroxide in de-ionized water (10 min). Next, slices were washed twice in running tap water and immersed in citrate buffer (pH 6) during 12 min at 126°C for antigen retrieval. After washing with TBS, slices were incubated with the primary antibodies (listed in Table 2) during 1 h at room temperature except for dynorphin for which the incubation was overnight at 4°C. After three washings with TBS, sections were incubated in secondary antibody during 30 min at room temperature and immunoreactivity (IR) signal was developed with DAB (3,3′-diaminobenzidine). Haematoxylin was used to counterstain nuclei and sections

were analysed using a Zeiss Axioplan bright-field microscope. For all antibodies, negative controls were obtained by omitting the primary antibody and positive controls by staining known immunopositive tissues [2, 22, 28]. For SV2A, SV2B and SV2C, brain tissue from knockout mice was also used as negative control [2, 5, 13].. Additional negative and positive controls 4-Aminobutyrate aminotransferase were carried out for SV2C. The consistent positive staining of the striatum and pallidum in the mouse and the human was used as a positive control (supplementary data Figure S1a). Western blot analysis (see supplementary material and methods) on pallidum extracts showed that the protein identified by the polyclonal antibody had the expected molecular weight of 82 kDa according to the antibody manufacturer, and presented as a heterogeneous set of bands due to its N-glycosylation as previously reported [2] (supplementary data Figure S1b). The positive immunostaining in the pallidum was not seen anymore after specific blocking with SV2C recombinant peptide at 100 ng/ml (SYSY®, Goettingen, Germany). Moreover, NCBI blast of protein sequence (http://blast.ncbi.nlm.nih.gov/Blast.

He was diagnosed as having CMV colitis by examination of the resected specimen, and we used gancyclovir to treat this infection. Subsequently, his renal function recovered and he no longer required hemodialysis on the 22nd day. He was discharged on the 30th day. Conclusion: It is noteworthy that CS is a complication of PCPS and that massive blood transfusion can cause CMV infection.

LIM LEE-MOAY1, KUO MEI-CHUAN1,2, HUNG CHI-CHIH1, TSAI YI-CHUN1, CHIU YI-WEN1,2, CHEN HUNG-CHUN1,2 1Division of Nephrology, Department of Internal selleck Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan www.selleckchem.com/products/VX-770.html Introduction: Fluid overload is frequently seen in critical ill patient especially those with acute kidney injury (AKI). AKI patients who required renal replacement therapy have different short-term and long-term outcomes, including the recovery of renal function and free from dialysis treatment. The aim of this study was to analyze the impact of fluid overload

and renal outcomes in AKI patients receiving renal replacement therapy. Methods: All AKI patients receiving emergent hemodialysis treatment in the dialysis unit of KMUH from February 1st, 2010 till March 30th, 2012 were included. Volume status of each patient was measured using a Body Composition Monitor (BCM). This procedure was conducted just before

the AKI patient received their 1st hemodialysis treatment. AKI was defined according to the RIFLE classification, utilizing the serum creatinine criteria. Baseline creatinine was the nadir serum creatinine level value 30 days before the index admission. Patients were divided into tertiles according to their OH/Body weight (BW) measurements. The primary outcome was recovery of renal function to dialysis independent during the index Meloxicam admission. Results: A total of 67 patients were included in this study. The mean age of our patients were 71.32 ± 13.68 years-old. Patients with higher OH/BW values were younger; most with diabetes mellitus, much lower in serum white blood cell count and albumin level. Higher body mass index and lower serum albumin were related to over-hydration in our patients. Fluid overload is prominent in patients with non-recovery in renal function with odd ratios of 8.04 (95% CI: 1.02–63.41, P < 0.05). Conclusion: Fluid balance should be regarded as a potentially valuable biomarker in critical illness, particularly in patients with AKI. Volume status evaluation by BCM provides a more accurate measurement of fluid status and prompt diagnosis of fluid overload in AKI patients.

8.1 ± 8.7 (mean ± SD). Likewise, Quality of Life and functional independence scores were significantly higher in patients on prophylaxis Selleckchem Torin 1 as compared to on-demand treatment. In conclusion, the study outcomes confirmed our hypothesis. Longer term prophylactic factor administration during childhood and adolescence prevents joint destruction.

“
“Department of Biotechnology, Israel Institute for Biological Research, Ness-Ziona, Israel Coagulation factor IX (FIX) is a serine protease that plays a pivotal role in the blood coagulation cascade. FIX deficiency leads to a blood clotting disorder known as haemophilia B. FIX, synthesized as a prepro-peptide of 461 amino acids, is processed and secreted into plasma. The protein undergoes numerous modifications, including, but not limited to glycosylation, γ-carboxylation and disulphide bond formation. Upon processing and limited proteolysis, the protein is converted into an active protease. Under physiological conditions, the FIX zymogen is a monomer. The purpose of this work was to analyse the conditions that may affect FIX monomeric state and promote and/or reduce oligomerization. Using native gel electrophoresis and size exclusion chromatography, we found that under decreased pH and ionic strength conditions, the FIX zymogen can oligomerize, resulting in the formation of higher molecular weight

species, Barasertib research buy with a concomitant reduction in specific activity. Similarly, FIX oligomers formed readily with low bovine serum albumin (BSA) concentrations; however, increased BSA concentrations

impeded FIX oligomerization. We hypothesize that normal blood physiological conditions are critical for maintaining active FIX monomers. Under conditions of stress associated with acidosis, electrolyte imbalance and low albumin levels, FIX oligomerization is expected to take place thus leading to compromised activity. Furthermore, albumin, Adenosine triphosphate which is commonly used as a drug stabilizer, may enhance the efficacy of FIX biological drugs by reducing oligomerization. “
“I joined National Institute of Biological Standards and Control (NIBSC) in 1974, but my introduction to the world of haemophilia had started some 8 years earlier, during my studies for a chemistry degree at Oxford University, when I met some patients with haemophilia during a short stay in the Churchill Hospital. I was impressed by the fortitude of these young patients who had had their lives severely disrupted by the disease, and intrigued to hear how little was known about their missing clotting factor, Factor VIII (FVIII). After I finished my degree I determined to pursue a career in coagulation, and eventually in 1969 I enrolled for a PhD at the Royal Free Hospital, under Katharine Dormandy. As a chemist I knew nothing about the intricacies of clotting tests and assays, and had to undertake a crash course.

The GPRD

is not population-based; therefore, its incidence estimate represents that of the GPRD and not the general population. Moreover, the code for PSC was not validated, and this poses additional challenges to its validity. These two studies were not fully comparable with the other studies included in the analysis. The incidence of PSC appears to be increasing; however, additional studies are necessary to confirm this observation. This increase in PSC incidence may be a direct result of its link to IBD because recent evidence suggests that the incidence of IBD is still increasing in many regions of the world.26, 29-32 Studies investigating the incidence of PSC with and without IBD may help to resolve this issue; however, the decrease in power when these analyses BTK inhibitor are conducted may hinder the finding of statistical evidence. One study reported

time trends in PSC with and without IBD but failed to find a statistically significant increase.9 Additionally, the observed increase may be due to improvements in the diagnostic abilities of physicians and diagnostic tools such as noninvasive imaging (i.e., SAHA HDAC magnetic resonance cholangiopancreatography).33, 34 Magnetic resonance cholangiopancreatography permits fast and highly accurate imaging of the biliary tree and has been used with increasing frequency as a noninvasive alternative to endoscopic retrograde cholangiopancreatography.33, 35-37 Furthermore, the increasing use of biological therapies (e.g., infliximab) and immunosuppressants (e.g., azathioprine

and methotrexate), particularly in those with IBD,38-40 may have contributed to the greater detection of PSC over time. Biologics and immunosuppressants have been associated with drug-induced liver complications, hepatobiliary disease, and liver toxicity41, 42; therefore, the routine screening of liver function profiles for individuals taking these therapies has increased. Studies investigating the incidence of PSC should consider assessments of diagnostic tool utilization over time. Moreover, this increase in incidence may be a result of biases in observational studies. In particular, the study by Escorsell et al.7 Thymidylate synthase had an unrealistically high AAPC of 27%. Many factors likely contributed to the obvious bias of this estimate. The population estimate used to calculate the incidence was taken from the end of the study period. An increase in the study population (i.e., 12 regions in Spain)43 over the time interval would have overestimated the increase in IR. Additionally, because of the retrospective nature of the study and the need for physicians to respond to a questionnaire, the response rate could have been lower for earlier time periods. Finally, detection bias could have been more pronounced at the end of the study period because of the increased availability and use of diagnostic technologies.

The published experience of inhibitors in previously treated patients (PTPs) informs the number of new inhibitors per cohort that are acceptable in a clinical trial. However, a single acceptable limit of new inhibitors fails to recognize the heterogeneity of inhibitors and their variable impact on clinical care. This review will discuss the published literature

on epidemiology and clinical characteristics of inhibitors and possible risk factors for formation in PTPs. As factor products containing novel expressions Enzalutamide clinical trial of the factor VIII (FVIII) gene are developed, a major concern is increased antigenicity leading to an anti-FVIII inhibitory antibody response. Accordingly, assessment of the risk of inhibitor formation is a major focus of the clinical development of novel FVIII products. In 1999, the International Society of Thrombosis and Haemostasis Scientific Subcommittee recommended the focused enrolment of previously treated patients (PTPs), defined as >150 lifetime exposure days, in initial clinical studies evaluating novel FVIII products [1]. This recommendation is based on the observed low rate

of inhibitor formation after extensive exposure to FVIII which facilitates detection of inhibitor induction by the new factor product, presumably resulting from exposure of neo-epitopes on the novel FVIII product under investigation. Vismodegib mw Although the rate of new inhibitor formation after >150 days is small, it is Endonuclease not zero; thus, knowledge of the baseline rate of inhibitor formation in

the PTP population is necessary to determine the upper acceptable limit of inhibitor development in clinical studies. Also important to this discussion is the clinical impact of new inhibitors in PTPs. Inhibitors that are limited in duration and do not require a change in the therapeutic approach to bleeding are the least clinically relevant, whereas those that are high responding, persistent and increase the propensity to bleed are the most troublesome. This report reviews what is known about inhibitor formation in patients who have previously received FVIII. Despite the definition of PTP in 1999, the term has been used to represent patients with a variety of prior exposures to FVIII concentrates ranging from a single exposure day to >250 days of exposure. A lack of standardization of the term PTP has led to many varied reports of the incidence of inhibitor formation in this population. Several reports have evaluated cohorts of patients switched from one product to another. Three such studies have identified markedly increased rates of inhibitor formation in PTPs.

Data were analyzed using the ΔΔCT method and normalized to 18S RNA. Immunohistochemical staining of tissue samples is described in Supporting selleck compound Materials. Cytokine expression was assayed using the Proteome Profiler Mouse Cytokine Array (R&D Systems). Membranes were detected with streptavidin-Alexa 700 (Invitrogen) using a two-channel near-infrared Odyssey scanner (LI-COR, UK), and spot intensities were quantified using software developed by our laboratory. CCL2 was quantified using the mouse CCL2 (monocyte chemoattractant

protein-1) enzyme-linked immunosorbent assay kit (eBioscience). Data are expressed as the mean ± SEM and were analyzed using an unpaired Student t test or one-way analysis of variance (ANOVA) with a Bonferroni posttest. Correlation

coefficients were calculated using nonparametric Spearman correlation analysis. P ≤ 0.05 was considered statistically significant. Macroscopic liver metastases were observed 7 days after MC38GFP+ inoculation into C57BL/6 mice (Supporting Fig. 1A). CD11b+ myeloid cells in tumor-bearing livers were assessed via FACS analysis and were segregated based on Gr1 (Ly6G/Ly6C) expression (Supporting Fig. 1B). Three discrete subsets, subsequently described as CD11b/Gr1high, CD11b/Gr1mid, and CD11b/Gr1low cells (Fig. 1A), were identified at day 0, 7, and 14, respectively (Supporting Fig. 1C). These subsets were further Dorsomorphin mw characterized by morphology (Fig. 1B) and surface marker expression (Fig. 1C). CD11b/Gr1high cells had multilobed nuclei typical of granulocytes, whereas CD11b/Gr1mid and CD11b/Gr1low cells had ovoid nuclei typical of monocytes/macrophages (Fig. 1B). All CD11b/Gr1 subsets expressed Ly6C and CCR5, but F4/80 was detected only on CD11b/Gr1mid cells and Ly6G was detected only on CD11b/Gr1high cells. CD11b/Gr1low cells had bimodal expression of CD11c, CCR4, and CXCR4, and both CD11b/Gr1mid and CD11b/Gr1low cells expressed CCR2. VEGFR1 and CCR1, previously reported to be expressed by myeloid cells infiltrating lung9 and liver metastases,13 were not detected

in any of the CD11b/Gr1 Vasopressin Receptor subsets (Fig. 1C). These subsets were negative for natural killer cell, T cell, and B cell markers (Supporting Fig. 1D). CD11b/Gr1mid and CD11b/Gr1low cells had similar cytokine messenger RNA profiles, with relatively high expression of proinflammatory mediators CCL2, CCL3, CCL5, interleukin (IL)-1α, IL-1β, IL-15, IL-18 and tumor necrosis factor (Fig. 1D), resembling a mixed M1/M2-like phenotype.14 CD11b/Gr1high cells expressed proinflammatory IL-1β, but expression of other cytokines was low. We then compared myeloid subsets in tumor-bearing and naïve livers. CD11b/Gr1mid percentages increased significantly 14 days after MC38GFP+ inoculation. A more modest increase in CD11b/Gr1low cells was observed, but CD11b/Gr1high cells remained constant (Fig. 2A).

Therefore, we limited the GCV treatment to 11 days administered selleck compound once-daily IP. Based on its pharmacokinetics, toxic serum levels of GCV are expected to be of a much

shorter duration, therefore minimizing adverse effects. Indeed, we did not observe increased lethality or mortality, or altered small bowel pathology, with our treatment scheme. Once in vivo HSC depletion was achieved, its functional effect was assessed by measuring markers of HSC activation. There was a dramatic decrease in α-SMA-positive cells in Tg mice undergoing HSC depletion, together with other markers of HSC proliferation (i.e., β-PDGFR and collagen I), indicating that depletion affected those HSCs most critical to fibrogenesis and repair (i.e., activated HSCs). Of interest, CXCR4 expression was also decreased in Tg mice undergoing HSC depletion. This cytokine receptor is another feature of activated HSCs, which also contributes to profibrogenic and proliferative C646 chemical structure responses.17 The findings reinforce the rationale for therapeutic HSC depletion, albeit not necessarily by a suicide-gene strategy. Moreover, not only was fibrosis reduced, but acute damage was attenuated, suggesting that depletion

of activated HSCs could have dual salutary effects on both the amount of fibrosis and extent of injury. Correlated with attenuated Astemizole injury was a reduction in 4-HNE consistent with decreased oxidant stress, although the source(s) of these pro-oxidants in both WT and Tg mice are not clarified by our findings. Specifically, reduction in 4-HNE could reflect decreased release by HSCs because of their depletion, or loss of paracrine signals from HSCs to other cell types that generate 4-HNE, including hepatocytes or inflammatory cells. Moreover, 4-HNE interacts directly with c-Jun N-terminal kinase (JNK) isoforms in human HSCs to stimulate procollagen type I expression and synthesis.21 Thus, reduced collagen production could also result from a feedback loop in which less 4-HNE leads to less JNK-mediated collagen expression. Of note, previous

studies using gliotoxin did not uncover an effect of HSC depletion on injury,2, 5 possibly because effects of gliotoxin are not as specific, and concurrent effects of gliotoxin on other cell types might have attenuated the phenotype. The mechanism of attenuated injury in the setting of HSC depletion is not fully clarified, but the increase in IL-10 and IFN-γ likely contribute to reduced injury, because these two cytokines both down-regulate HSC activation and fibrosis production.22 Polychromatic flow cytometry for intrahepatic immune cell populations revealed increased numbers of well-known cellular sources of IL-10 (Tregs and monocytes)23 as well as for IFN-γ (DC, NK, and CD4+ and CD8+ T cells).

Collagen type I protein in the supernatant of purified/serum HBV group also increased compared to the control group (408.0 ± 8.0/384.4 ± 6.8

vs 262.7 ± 15.7 ng/mL, P < 0.05). However, the 3 × 107 IU/mL purified/serum HBV increased collagen type I expression similar to that of 3 × 105 IU/mL, while 3 × 103 IU/mL group showed no effect. Human HBV immunoglobulin alleviated HBV-induced collagen I expression, but no evidence of HBV infection was found. Neutralization of transforming growth factor beta, tumor necrosis factor alpha, platelet-derived growth factor, extracellular signal-regulated kinase and TGF-β receptor had no obvious inhibitory effects; only inhibition of p38 check details mitogen-activated protein kinase decreased collagen type I mRNA expression by 0.5-/0.4- and 0.4-/0.3-fold at 24 and 48 h, respectively.

It reduced collagen type I protein in the purified/serum HBV group for 48 h (252.1 ± 14.1/251.7 ± 18.8 vs 403.9 ± 4.9/385.0 ± 4.2 ng/mL, P < 0.05). Conclusion:  HBV directly promotes collagen type I expression of LX-2 cells without infection in vitro. "
“Hepatocellular SP600125 molecular weight carcinoma (HCC) is one of the most common neoplasms worldwide. The recent dramatic increase of HCC cases is associated with chronic hepatitis B and C.[1] Worldwide, there are 300 million people infected with hepatitis B virus and 170 million with hepatitis C virus, respectively. Prothrombin, a 72-kDa plasma protein, is synthesized in hepatocytes as a precursor with 10 glutamic acid (Glu) Vasopressin Receptor residues. Under physiological condition, these Glu residues are converted into gamma-carboxy glutamic acid (Gla) by gamma-glutamylcarboxylase, which uses

vitamin K as a cofactor. However, when gamma-glutamylcarboxylation is impaired, Glu residues of prothrombin remain unconverted, and a des-carboxy prothrombin (DCP) is released into the bloodstream as a result. DCP is elevated in many patients with HCC, as well as those with vitamin K deficiency, so that raised plasma DCP can result from the administration of vitamin K antagonists like warfarin or impaired uptake of vitamin K in cholestasis with hyperbilirubinemia. Plasma level lf DCP is significantly elevated in patients with HCC, and is a clinically established HCC marker. For small tumors, measurement of both alpha fetoprotein (AFP) and DCP is recommended, because DCP is more specific for HCC than AFP. DCP is potentially valuable primarily as a prognostic biomarker, which would be predictive of rapid tumor progression and provide information about a possible poor prognosis.[2] This is because DCP-positive HCCs show aggressive and invasive distinctiveness. A high DCP level implies a poor prognosis, and a slight increase in the DCP concentration after therapy could suggest recurrence.[2] Kiriyama et al. demonstrated significantly poorer prognosis in “triple-positive” HCC patients, who were positive for all three available serum HCC markers, AFP, AFP-L3, and DCP.

Plasma ribavirin determinations may help to resolve this. Variability in ribavirin dosage due to dose reduction or treatment adherence did not appear to be a confounding factor, because we identified favorable virological responses in anemic patients despite significantly lower mean ribavirin exposure during the first 24 Poziotinib purchase weeks of therapy (Table 2). Individual pharmacokinetic responses to ribavirin may be related to recently described variants in the inosine triphosphatase (ITPA) gene that result in ITP deficiency and therefore protection against ribavirin-induced

anemia.11 Precisely how ITP deficiency interacts with the mechanisms leading to ribavirin-induced anemia remains unclear. Interestingly, no association of ITPA variants with rapid or sustained virological response to PEG-IFN and ribavirin was identified by Fellay and colleagues,12 although a trend for increased SVR was observed when patients were stratified by interleukin-28b genotype, which is a strong predictor of treatment outcome. Although we found significant relationships with both anemia and hemoglobin decline >30 g/L during therapy and higher SVR, the proportion of patients who developed a hemoglobin Doxorubicin ic50 decline >30 g/L was considerably greater, suggesting that the absolute decline in hemoglobin may be more clinically relevant. In this regard, the identification

of a subset of patients with rapid hemoglobin decline who do not benefit Montelukast Sodium in terms of improved SVR provides useful information for prediction of outcome and potential opportunities for interventional strategies such as erythropoietin. Furthermore, the relationship between hemoglobin decline and treatment response remained highly significant following adjustment for fibrosis

stage, with both factors being strongly associated with SVR in a multivariate model. Despite this, patients with cirrhosis had generally lower SVR rates than patients without cirrhosis as reported in the CHARIOT study, an outcome that did not appear to relate to lower ribavirin adherence.13 In conclusion, we have shown that the odds of achieving an SVR for patients with HCV genotype 1 infection who develop anemia or who experience a decline in hemoglobin >30 g/L, even if they do not become anemic, are approximately twice that of those who do not develop similar hematological changes. This relationship was identified with or without the inclusion of 14 patients who received erythropoietin. However, patients with hemoglobin concentrations >120 g/L, those with a >30 g/L decline within the initial 4 weeks of therapy, and those with decline >60 g/L from baseline during therapy do not achieve similar virological benefits. “
“Jaundice in patients with AIDS can be a result of diverse conditions ranging from opportunistic infections to drug-related hepatotoxicity.