Continuous engagement of a self-specific activation receptor induces NK cell tolerance

Natural killer (NK) cell tolerance mechanisms are incompletely understood. One possibility is that they possess self-specific activation receptors that result in hyporesponsiveness unless modulated by self–major histocompatability complex (MHC)–specific inhibitory receptors. As putative self-specific activation receptors have not been well characterized, we studied a transgenic C57BL/6 mouse that ubiquitously expresses m157 (m157-Tg), which is the murine cytomegalovirus (MCMV)–encoded ligand for the Ly49H NK cell activation receptor. The transgenic mice were more susceptible to MCMV infection and were unable to reject m157-Tg bone marrow, suggesting defects in Ly49H⁺ NK cells. There was a reversible hyporesponsiveness of Ly49H⁺ NK cells that extended to Ly49H-independent stimuli. Continuous Ly49H–m157 interaction was necessary for the functional defects. Interestingly, functional defects occurred when mature wild-type NK cells were adoptively transferred to m157-Tg mice, suggesting that mature NK cells may acquire hyporesponsiveness. Importantly, NK cell tolerance caused by Ly49H–m157 interaction was similar in NK cells regardless of expression of Ly49C, an inhibitory receptor specific for a self-MHC allele in C57BL/6 mice. Thus, engagement of self-specific activation receptors in vivo induces an NK cell tolerance effect that is not affected by self-MHC–specific inhibitory receptors.     

Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress

Background  

Recent studies have demonstrated a link between the inflammatory response, increased cytokine formation, and neurodegeneration in the brain. The beneficial effects of anti-inflammatory drugs in neurodegenerative diseases, such as Alzheimer's disease (AD), have been documented. Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti-inflammatory properties. The objectives of this study are to determine the effects of acetaminophen on cultured brain neuronal survival and inflammatory factor expression when exposed to oxidative stress.     

Systemic adjuvant therapy for breast cancer.

Systemic therapy for operable breast cancer can delay the time to recurrence. Recurrence of breast cancer can follow a variable clinical course but will lead to death in virtually all cases. This delay is reflected in an accompanying improvement in overall survival with treatment. Almost 35 years have passed since the introduction of adjuvant chemotherapy, whereas adjuvant tamoxifen trials were begun 17 years ago. In that time, only in a minority of patients has a clear consensus emerged on the appropriate use of adjuvant therapies. Overview analysis from large numbers of controlled clinical trials has produced a much larger data base for examining the effects of hormonal and cytotoxic therapy on the outcome of patients with early-stage breast cancer and provides greater statistical power to detect small differences in particular subgroups of patients, which may not have been apparent in individual studies. Patients with involved lymph nodes are now routinely treated with chemotherapy if they are premenopausal and with tamoxifen if they are postmenopausal, especially if their tumors contain estrogen receptor. More recent trials attempt to examine the use of these therapies outside of these prescribed groups as well as the introduction of new chemotherapeutic agents and dosage regimens, some of which are based on biologic principles of alternating, non-cross-resistant therapy and dose responsiveness. Treatment of node-negative breast cancer remains controversial. Small but real differences in odds of relapse have emerged with adjuvant treatment, although the nature of the risks and benefits remains to be defined.     

Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer

This review describes woodchucks chronically infected with the woodchuck hepatitis virus (WHV) as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma (HCC) induced by the hepatitis B virus (HBV). Since laboratory animal models susceptible to HBV infection are limited, woodchucks experimentally infected with WHV, a hepatitis virus closely related to HBV, are increasingly used to enhance our understanding of virus-host interactions, immune response, and liver disease progression. A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established, which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans. HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size, morphology, and molecular gene signature to those of HBV-infected patients. Accordingly, woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC. In addition, drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs, alone or in combination with other compounds, minimizes the risk of liver disease progression to HCC. More recently, woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute, self-limited and chronic infections. Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae, including the onset of HCC. Therefore, woodchucks with chronic WHV infection constitute a well-characterized, fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities, which are based on chemo, gene, and immune therapy, for the prevention and treatment of HCC in patients for which current treatment options are dismal.     

Propensity-matched analysis of association between preoperative anemia and in-hospital mortality in cardiac surgical patients undergoing valvular heart surgeries

Introduction:

Anaemia is associated with increased post-operative morbidity and mortality. We retrospectively assess the relationship between preoperative anaemia and in-hospital mortality in valvular cardiac surgical population.

Materials and Methods:

Data from consecutive adult patients who underwent valvular repair/replacement at our institute from January 2010 to April 2014 were collected from hospital records. Anaemia was defined according to WHO criteria (hemoglobin <13g/dl for males and <12g/dl for females). 1:1 matching was done for anemic and non-anemic patients based on propensity for potentially confounding variables. Logistic regression was used to evaluate the relationship between anaemia and in-hospital mortality. MatchIt package for R software was used for propensity matching and SPSS 16.0.0 was used for statistical analysis.

Results:

2449 patients undergoing valvular surgery with or without coronary artery grafting were included. Anaemia was present in 37.1% (33.91% among males & 40.88% among females). Unadjusted OR for mortality was 1.6 in anemic group (95% Confidence Interval [95% CI] – 1.041-2.570; p=0.033). 1:1 matching was done on the basis of propensity score for anaemia (866 pairs). Balancing was confirmed using standardized differences. Anaemia had an OR of 1.8 for mortality (95% CI- 1.042 to 3.094, P=0.035). Hematocrit of < 20 on bypass was associated with higher mortality.

Conclusion:

Preoperative anaemia is an independent risk factor associated with in-hospital mortality in patients undergoing valvular heart surgery.     

Tarlov cysts: a report of two cases

Perineural cysts are common and usually detected incidentally during magnetic resonance imaging of the lumbosacral spine. Treatment is indicated only when the cyst is symptomatic. We report one such patients presented with cauda equina syndrome and another with low back pain with claudication. They underwent excision and duraplasty; both motor and sensory fibres were carefully separated from the cyst wall using a nerve root retractor and penfield. There was no nerve root damage or neural deficit. Symptoms were relieved postoperatively.