A systematic review of immunosuppressant adherence interventions in transplant recipients: Decoding the streetlight effect

Non‐adherence to immunosuppressant medications is an important risk factor for graft dysfunction. To evaluate the effectiveness of adherence‐enhancing interventions, we reviewed adherence intervention studies in solid organ transplant recipients (all ages). Using the following databases: PsycINFO, PubMed, Scopus, and ScienceDirect, we identified 41 eligible studies. Only three non‐randomized trials showed a possible positive effect on objective indicators of transplant outcomes (such as rejection, liver enzyme levels, kidney function). None of the 21 RCTs showed an improvement in transplant outcomes. Three studies showed a higher rate of adverse events in the intervention group as compared with controls, although this may be related to ascertainment bias. Improvement in adherence as measured indirectly (eg, with electronic monitoring devices) was not aligned with effects on transplant outcomes. We conclude that adherence interventions, to date, have largely been ineffective in improving transplant outcomes. To improve this track record, intervention efforts may wish to concentrate on non‐adherent patients (rather than use convenience sampling, which excludes many of the patients who need the intervention), use direct measures of adherence to guide the interventions, and employ strategies that are intensive and yet engaging enough to ensure that non‐adherent patients are able to participate.     

Adjuvant potential of aggregate-forming polyglutamine domains

Aggregation may significantly affect the fate of a polypeptide, including its susceptibility to proteasome-dependent or autophagic degradation, its interaction with chaperones, etc. Since all these factors may affect the antigenicity of a polypeptide, we hypothesized that stimulating aggregation of an antigenic protein by its fusion to polyQ domain may enhance its antigenic potential. This hypothesis was tested with the weakly immunogenic model antigen GFP, which was fused to either long polyQ domain that triggers protein aggregation (103Q), or short polyQ domain that does not promote aggregation (25Q). Plasmids encoding control pGFP or soluble 25Q-GFP generated a very weak antibody response, while a significant increase in anti-GFP antibody titer was seen in groups immunized with DNA encoding aggregating 103Q-GFP. Similarly, fusion with 103Q strongly enhanced anti-GFP CTL activity, compared to fusion with 25Q. No apparent toxicity was observed after immunization with polyQ-GFP fusions. These data suggest that fusion of an antigen with expanded polyQ domains could have a significant adjuvant potential.     

Update on progressive familial intrahepatic cholestasis

Three distinct forms of familial intrahepatic cholestasis are the result of mutations in the ATP8B1, ABCB11, and ABCB4 genes. The pathophysiologies of the latter 2 of these diseases are well characterized and are the result of abnormalities in canalicular excretion of bile acids and phospholipids, respectively. The molecular pathophysiology of the systemic disease associated with mutations in ATP8B1 remains unclear. In all of these diseases, wide variations in clinical phenotypes have been observed. The variability can be ascribed at least in part to predicted genotype:phenotype correlations. Disease- and genotype-specific prognoses and therapeutic approaches may exist, although much more information needs to be ascertained before clinicians can confidently make decisions based on genetic information.     

Broad-spectrum anti-tumor and anti-metastatic DNA vaccine based on p62-encoding vector

Autophagy plays an important role in neoplastic transformation of cells and in resistance of cancer cells to radio- and chemotherapy. p62 (SQSTM1) is a key component of autophagic machinery which is also involved in signal transduction. Although recent empirical observations demonstrated that p62 is overexpressed in variety of human tumors, a mechanism of p62 overexpression is not known. Here we report that the transformation of normal human mammary epithelial cells with diverse oncogenes (RAS, PIK3CA and Her2) causes marked accumulation of p62. Based on this result, we hypothesized that p62 may be a feasible candidate to be an anti-cancer DNA vaccine. Here we performed a preclinical study of a novel DNA vaccine encoding p62. Intramuscularly administered p62-encoding plasmid induced anti-p62 antibodies and exhibited strong antitumor activity in four models of allogeneic mouse tumors – B16 melanoma, Lewis lung carcinoma (LLC), S37 sarcoma, and Ca755 breast carcinoma. In mice challenged with Ca755 cells, p62 treatment had dual effect: inhibited tumor growth in some mice and prolonged life in those mice which developed tumor size similar to control. P62-encoding plasmid has demonstrated its potency both as a preventive and therapeutic vaccine. Importantly, p62 vaccination drastically suppressed metastasis formation: in B16 melanoma where tumor cells where injected intravenously, and in LLC and S37 sarcoma with spontaneous metastasis. Overall, we conclude that a p62-encoding vector(s) constitute(s) a novel, effective broad-spectrum antitumor and anti-metastatic vaccine feasible for further development and clinical trials.     

Abernethy malformation complicated by hepatopulmonary syndrome and a liver mass successfully treated by liver transplantation

Osorio MJ, Bonow A, Bond GJ, Rivera MR, Vaughan KG, Shah A, Shneider BL. Abernethy malformation complicated by hepatopulmonary syndrome and a liver mass successfully treated by liver transplantation.
Pediatr Transplantation 2011: 15: E149–E151. © 2010 John Wiley & Sons A/S. Abstract: A seven‐yr‐old boy presented with persistent oxygen requirement following a respiratory infection. Physical exam was remarkable for orthodeoxia and digital clubbing. Laboratory evaluation showed elevated A‐a oxygen gradient of 48 mmHg and mildly elevated transaminases. Sonography showed a 13 cm multilobulated liver mass and a biopsy revealed histological findings consistent with focal nodular hyperplasia. MAA scan revealed 23% right to left shunting. Abdominal CTA and MRV demonstrated the absence of the intrahepatic portal vein with an extrahepatic portocaval shunt. Abernethy malformation is a rare anomalous intra‐ or extrahepatic communication between portal blood flow and systemic venous return. In rare cases, Abernethy malformation results in HPS. Ours is the sixth case report to describe the co‐existence of these two entities. Surgical correction of anomalous hepatic vasculature or liver transplant is imperative to restoration of lung function and also to prevent progression of possible malignant liver tumors. We describe the second patient with Abernethy and HPS who underwent liver transplant with complete resolution of HPS.     

A comparative study of the different diagnostic criteria of gestational diabetes mellitus and its incidence

Background

High prevalence of diabetes and genetic predisposition to metabolic syndrome among Indians places Indian women at risk to develop gestational diabetes mellitus (GDM) and its complications. Literature defines multiple criteria for GDM. This prospective study compares available diagnostic criteria for GDM in Indian women and their correlation with perinatal morbidity.

Method

Nine hundred and forty-eight consecutive voluntary nondiabetic pregnant women were recruited for the study. Seven hundred and twenty-three of these (mean age 23.45 years; 75.7% < 25 years) who reported for the follow-up were screened for GDM at 24–28 weeks gestation by American College of Obstetrics and Gynaecology (ACOG) guidelines and World Health Organization (WHO) criteria. Glycated haemoglobin (HbA_1c) and fasting and two-hours postglucose plasma insulin levels were also analysed. Pregnancy outcome was known for 291 of these. Concordance of risk factors and perinatal complications was analysed with respect to GDM.

Results

Prevalence of GDM at 24–28 weeks gestation was found to be 4.8% by WHO criteria, 6.36% by Carpenter and Coustan''s criteria, and 3.5% by O''Sullivan''s criteria. Prevalence was marginally higher in women of higher age, having past history of abortion or family history of diabetes mellitus (DM) (P > 0.05). None of these women had HbA_1c > 6%. Relative risk of abnormal delivery (pregnancy outcome) was 1.93, 1.39, and 1.17 in women with GDM by O''Sullivan''s, WHO, and Carpenter''s criteria, respectively (P > 0.05). Abnormal deliveries were marginally higher in women with high postglucose load insulin levels. Mean weight of the newborns was essentially the same in GDM and nonGDM women by any of the criteria. One-hour and two-hours postglucose values were more sensitive in diagnosing GDM by O''Sullivan''s criteria while fasting plasma glucose value had the poorest specificity with 2.5% of nonGDM women having values above the cut-off. Modifications of these criteria did not im-prove their predictive value for abnormal delivery over that of O''Sullivan''s criteria.

Conclusion

Prevalence of GDM and abnormal delivery in women < 35 years of age is low. Therefore, global screening for GDM may not be very useful in women < 25 years of age unless family history of DM or past history of abortion is present. Existing evidence is inadequate to justify the switchover from O''Sullivan''s criteria for diagnosis of GDM.Key Words: Carpenter''s criteria, GDM, O''Sullivan''s criteria, WHO criteria     

A comparative study of the different diagnostic criteria of gestational diabetes mellitus and its incidence

Background

High prevalence of diabetes and genetic predisposition to metabolic syndrome among Indians places Indian women at risk to develop gestational diabetes mellitus (GDM) and its complications. Literature defines multiple criteria for GDM. This prospective study compares available diagnostic criteria for GDM in Indian women and their correlation with perinatal morbidity.

Method

Nine hundred and forty-eight consecutive voluntary nondiabetic pregnant women were recruited for the study. Seven hundred and twenty-three of these (mean age 23.45 years; 75.7% < 25 years) who reported for the follow-up were screened for GDM at 24–28 weeks gestation by American College of Obstetrics and Gynaecology (ACOG) guidelines and World Health Organization (WHO) criteria. Glycated haemoglobin (HbA_1c) and fasting and two-hours postglucose plasma insulin levels were also analysed. Pregnancy outcome was known for 291 of these. Concordance of risk factors and perinatal complications was analysed with respect to GDM.

Results

Prevalence of GDM at 24–28 weeks gestation was found to be 4.8% by WHO criteria, 6.36% by Carpenter and Coustan's criteria, and 3.5% by O'Sullivan's criteria. Prevalence was marginally higher in women of higher age, having past history of abortion or family history of diabetes mellitus (DM) (P > 0.05). None of these women had HbA_1c > 6%. Relative risk of abnormal delivery (pregnancy outcome) was 1.93, 1.39, and 1.17 in women with GDM by O'Sullivan's, WHO, and Carpenter's criteria, respectively (P > 0.05). Abnormal deliveries were marginally higher in women with high postglucose load insulin levels. Mean weight of the newborns was essentially the same in GDM and nonGDM women by any of the criteria. One-hour and two-hours postglucose values were more sensitive in diagnosing GDM by O'Sullivan's criteria while fasting plasma glucose value had the poorest specificity with 2.5% of nonGDM women having values above the cut-off. Modifications of these criteria did not im-prove their predictive value for abnormal delivery over that of O'Sullivan's criteria.

Conclusion

Prevalence of GDM and abnormal delivery in women < 35 years of age is low. Therefore, global screening for GDM may not be very useful in women < 25 years of age unless family history of DM or past history of abortion is present. Existing evidence is inadequate to justify the switchover from O'Sullivan's criteria for diagnosis of GDM.