Interactions between human microbiome,liver diseases,and immunosuppression after liver transplant

In liver transplant patients, solid tumors and post-transplant lymphoproliferative disorders have emerged as significant long-term mortality causes. In addition, it is assumed that de novo malignancy after liver transplantation (LT) is the second-leading cause of death after cardiovascular complications. Well-established risk factors for post-transplant lymphoproliferative disorders and solid tumors are calcineurin inhibitors, tacrolimus, and cyclosporine, the cornerstones of all immunosuppressive therapies used after LT. The loss of immunocompetence facilitated by the host immune system due to prolonged immunosuppressive therapy leads to cancer development, including LT patients. Furthermore, various mechanisms such as bacterial dysbiosis, activation through microbe-associated molecular patterns, leaky gut, and bacterial metabolites can drive cancer-promoting liver inflammation, fibrosis, and genotoxicity. Therefore, changes in human microbiota composition may contribute further to de novo carcinogenesis associated with the severe immunosuppression after LT.     

Psychopathological traits and 5-HT2A receptor promoter polymorphism (-1438 G/A) in patients suffering from Anorexia Nervosa and Bulimia Nervosa

Various studies have evaluated the possible role of the -1438G/A polymorphism within the 5-HT2A receptor gene in the susceptibility to Eating Disorders (EDs). One hundred and forty-eight ED patients (EDp) and 89 control subjects were interviewed by means of the Eating Disorder Examination (EDE) and analyzed for distribution of the -1438G/A polymorphism. Patients with the AA genotype suffering from Anorexia Nervosa and Bulimia Nervosa showed higher Weight and Shape Concern (P = 0.003 and P = 0.010, respectively) scores and greater overall severity of the ED psychopathology (EDE total score) (P = 0.012). The obtained preliminary data suggest the use of dimensional psychopathological measures in ED genetic studies.     

MCMV glycoprotein gp40 confers virus resistance to CD8+ T cells and NK cells in vivo

The susceptibility of certain inbred mouse strains to murine cytomegalovirus (MCMV) is related to their inability to generate a strong natural killer (NK) cell response. We addressed here whether the MCMV susceptibility of the BALB/c strain is due to viral functions that control NK cell activation in a strain-specific manner. MCMV expresses two proteins, gp48 and gp40, that are encoded by the genes m06 and m152, respectively; they down-regulate major histocompatibility complex (MHC) class I expression at the plasma membrane. Using MCMV deletion mutants and revertants, we found that gp40 but not gp48 controls NK cell activation. Absence of gp40 improved antiviral NK cell control in BALB/c, but not C57BL/6, mice. Down-regulation of H-60, the high-affinity ligand for the NKG2D receptor, was the mechanism by which gp40 modulates NK cell activation. Thus, a single herpesvirus protein has a dual function in inhibiting both the adaptive as well as the innate immune response.     

Huntingtin fragmentation and increased caspase 3, 8 and 9 activities in lymphoblasts with heterozygous and homozygous Huntington's disease mutation

Huntington's disease (HD) is caused by mutated huntingtin (htt), a toxic protein ubiquitously expressed in nervous and non-nervous system tissues. Fragmentation of htt by caspases and further accumulation in cells of protein aggregates contribute to cell dysfunction and death. In the attempt to elucidate whether this mechanism depends on patients' genotype, we analysed the pattern of htt fragmentation, the caspase 3, 8 and 9 activities and their variation in lymphoblasts with heterozygous and homozygous CAG mutation and in controls. Cells homozygous for expanded mutation showed greater amount of mutated fragments than heterozygotes and controls, caspase 3, 8 and 9 activities greater in mutated than control cell lines, after cyanide treatment, the caspase 3 and 8 particularly increased in homozygotes. This data offers a biological explanation to the clinical in-patients evidence of mutation homozygosity associated with more severe phenotype.     

Specificity of L1 peptides versus virus-like particles for detection of human papillomavirus-positive cervical lesions in females attending Engativa Hospital, Bogota, Colombia

A serological test for the detection of human papillomavirus (HPV) infection in females at risk of developing cervical cancer could be based on conserved L1 peptides with low levels of antigenicity specifically recognized by antibodies from patients with cervical lesions infected with high-risk HPV (HR-HPV) types. The aim was to assess the ability of L1 peptides 18283, 18294, and 18301 compared with the ability of virus-like particles (VLPs) to identify these infections in females. A total of 391 HPV-infected female volunteers were interviewed, and peripheral blood and cervical cells were obtained for detection of anti-HPV antibodies and HPV DNA; all of the patients had a Pap smear test; 287 patients were referred for colposcopy or biopsy, according to gynecological criteria. The level of agreement, as determined by the use of the Lin coefficient (rho value), showed that 75 to 83% of females with HR-HPV DNA-positive cervical lesions had antibodies that recognized VLPs and peptide 18283, 18294, or 18301, while 15 to 23% of the HPV DNA-negative females with a normal cytology had antibodies that recognized these three peptides and 45% had antibodies that recognized VLPs. The rate of agreement between peptides and VLPs for antibody detection was higher for patients with HPV DNA-positive cervical lesions. Peptides 18283, 18294, and 18301 showed similar sensitivities for the detection of HR-HPV DNA-positive cervical lesions and were more specific than VLPs. Peptide 18301 might be detecting protective antibodies in HPV DNA-negative females with atypical squamous cells of undetermined significance. These peptides could be useful for the design of a serology test for the detection of HR-HPV infection in females with cervical lesions and at risk of cervical cancer.     

Trunk lean gait modification and knee joint load in people with medial knee osteoarthritis: The effect of varying trunk lean angles

Objective

To evaluate whether increased lateral trunk lean toward the symptomatic lower extremity during gait in people with medial knee osteoarthritis (OA) immediately alters symptoms or medial knee load, as measured by the external knee adduction moment (KAM).

Methods

Participants with medial knee OA (n = 22) underwent 3‐dimensional gait analysis to measure KAM peaks (early and late stance) and KAM impulse. Following the analysis of natural gait, participants were trained to lean their trunk toward the symptomatic leg during ipsilateral stance over 3 randomly ordered conditions (6°, 9°, and 12° lean). A projection screen displayed real‐time trunk angles and target levels. Pain/discomfort in the knees, the hip, and the back were measured across conditions. Load‐modifying effects of increasing lean magnitudes were investigated using linear mixed models. Mediating effects of peak lean timing and participant characteristics (pain and malalignment) were evaluated.

Results

Increased trunk lean reduced all KAM measures (P < 0.001), with larger lean angles achieving greater reductions. Efficacy of load reduction improved with later peak lean timing for all measures of the KAM. Participant characteristics did not mediate the effect of trunk lean on the KAM, and symptoms did not change across conditions (P > 0.05).

Conclusion

Increased trunk lean reduced medial knee load in a dose‐response manner. Slightly later achievement of peak trunk lean improved the load‐modifying effect of this gait strategy. No immediate symptomatic changes were identified. Future research should determine if long‐term implementation of this gait strategy is feasible and whether it can modify disease symptoms and OA progression.