We report here results of clinical trials on a birth control vaccine, consisting of a heterospecies dimer of the .3 subunit of human chorionic gonadotropin (hCG) associated noncovalently with the a subunit of ovine luteinizing hormone and coijugated to tetanus and diphtheria toxoids as carriers, that induces antibodies of high avidity (Ka 1010 M-) against hCG. Fertile women exposed to conception over 1224 cycles recorded only one pregnancy at antibody titers of >50 ng/ml (hCG bioneutralization capacity). The antibody response declines with time; fertility was regained when titers fell to <35 ng/ml. This study presents evidence of the feasibility of a vaccine for control of human fertility.A number of contraceptive methods are available; they do not, however, suit all potential users. There is need to develop additional methods, in particular those that are reversible, require only periodic intake, and do not disturb menstrual regularity or bleeding. Vaccines regulating fertility offer promising prospects to meet these specifications. The rationale for these vaccines is to induce the formation of antibodies and/or cell-mediated immunity to intercept selectively a process critical to the success of reproduction. A number of potential antigens are being investigated (1-7). Among these are hormones, which play an important role in the regulation of fertility. Human chorionic gonadotropin (hCG) is an early signal of conception and is considered essential for establishment and maintenance of early pregnancy. An advantage in choosing hCG as a target for immunocontraception is that its inactivation would not interfere with other physiological processes in the female, such as ovulation and production of sex steroid hormones.Carrier conjugation with tetanus toxoid (TT) was proposed as a strategy to overcome the immunological tolerance of a woman against hCG (8). This initial prototype vaccine (/3hCG-TT adsorbed on alum) had limitations. It induced high antibody titers in only a small percentage of women, and those with low titers were not protected from pregnancy (9). Three changes were made to enhance immunogenicity.(i) An adjuvant, the sodium phthalyl derivative of lipopolysaccharide, was included in the first injection. This nonpyrogenic adjuvant is usable in aqueous phase (10). Its use doubled, on average, anti-hCG titers and increased the frequency of high responders.(ii) The intrinsic immunogenicity of (3hCG was enhanced by associating it noncovalently with the a subunit of ovine luteinizing hormone (LH) to form a heterospecies dimer (HSD), a laboratory-made hormone that attains a conformation which recognizes receptors on target tissues (whereas isolated subunits do not) and generates a steroidogenic response even superior to that by hCG (11). HSD linked to carriers was indeed found to be more immunogenic than ,8hCG in rats and monkeys (12). Moreover, the antibodies had better capacity to neutralize the bioactivity of hCG (11,13 It was important to determine whether the antibodies induced by the HSD-and 8hC...

Osteopontin (OPN) was first identified in 1986. The prefix osteo‐ means bone; however, OPN is expressed in other tissues, including liver. The suffix ‐pontin means bridge and denotes the role of OPN as a link protein within the extracellular matrix. While OPN has well‐established physiological roles, multiple “omics” analyses suggest that it is also involved in chronic liver disease. In this review, we provide a summary of the OPN gene and protein structure and regulation. We outline the current knowledge on how OPN is involved in hepatic steatosis in the context of alcoholic liver disease and non‐alcoholic fatty liver disease. We describe the mechanisms whereby OPN participates in inflammation and liver fibrosis and discuss current research on its role in hepatocellular carcinoma and cholangiopathies. To conclude, we highlight important points to consider when doing research on OPN and provide direction for making progress on how OPN contributes to chronic liver disease.

In patients with SAH, there is a significant increase in albumin oxidation, and albumin acts as a pro-oxidant; this promotes oxidative stress and inflammation in SAH patients through activation of neutrophils. (Hepatology 2017;65:631-646).

Acute-on-chronic liver failure (ACLF) is an ailment with high incidence of multiorgan failure (MOF) and consequent mortality. Dysregulated iron homeostasis and macrophage dysfunction are linked to increased incidence of MOF. We investigated whether a panel of circulating iron-regulating proteins are associated with development of MOF and can predict 15-or 30-day mortality in ACLF patients. One hundred twenty patients with ACLF, 20 patients with compensated cirrhosis, and 20 healthy controls were studied. Relative protein expression profiling was performed in the derivative cohort and confirmed in the validation cohort. A panel of iron regulators and indices were determined. Multiparametric flow cytometry for quantitation of labile iron pool (LIP) was performed. Validation studies confirmed lower serum transferrin (Tf) and ceruloplasmin levels in ACLF and ACLF-MOF, compared to patients with cirrhosis and controls (P < 0.01). Serum iron and ferritin levels were markedly elevated (P < 0.001; P < 0.05) and hepcidin levels were lower (P < 0.001) in ACLF patients with MOF than those without and other groups (P < 0.001). Percentage Tf saturation (%SAT) was higher in ACLF-MOF (39.2%; P < 0.001) and correlated with poor outcome (hazard ratio: 6.970; P < 0.01). Intracellular LIP indices were significantly elevated in the subsets of circulating macrophages in ACLF-MOF, compared to other groups (P < 0.01). Whereas expression of iron-regulatory genes was markedly down-regulated, genes related to endoplasmic reticulum stress, apoptosis, and inflammation were up-regulated in ACLF patients, compared to patients with cirrhosis. Severe dysregulation of autophagy mechanisms was also observed in the former. Conclusions: Iron metabolism and transport are severely deranged in ACLF patients and more so in those with MOF. %SAT, circulating hepcidin, and LIP in macrophages correlate with disease severity and %SAT could be used for early prognostication in ACLF patients. (HEPATOLOGY 2015;61:1306-1320

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