Anti-idiotypic antibodies to anti-HLA receptors induced by pregnancy

We have previously shown that lymphoblasts alloactivated in vitro acquire the capacity of stimulating the autologous mixed lymphocyte response. This response is anti-idiotypic in nature because lymphocytes so primed display accelerated memory responses only when restimulated by autologous lymphoblasts that have been alloactivated against the same HLA-DR antigen. Based on this observation we have postulated that the absence of HLA antibodies in alloimmunized human subjects may be due to the development of autoantibodies that react with the anti-HLA receptors expressed by primed lymphocytes or by anti-HLA antibodies or both. This hypothesis has been confirmed in the present investigations which show that sera from parous women react with autologous T lymphoblasts primed in 5-day mixed lymphocyte culture against their husband—i.e., with lymphoblasts expressing receptors for the immunizing donor. Anti-HLA receptors expressed by T and B lymphocytes seem to share serologic determinants because sera that bind to autologous alloactivated lymphoblasts are also capable of inhibiting the anti-HLA activity of autologous and homologous sera. Auto-anti-idiotypic antibodies inhibit the autologous mixed lymphocyte response to autologous alloactivated lymphoblasts, a phenomenon whose in vivo correlate may reside in autoinhibition of anti-HLA antibody formation and of allograft immunity. Because auto-anti-idiotypic antibodies were found in sera from all parous women tested, the hypothesis that nonresponsiveness to alloantigens exists as a state per se is not likely. The passive transfer of antireceptor (idiotype) immunity by use of antibodies from pregnant women's sera may provide a powerful tool for specific suppression of allograft rejection.     

Nicotinic Acid Metabolism, V. A Cobamide Coenzyme-Dependent Conversion of α-Methyleneglutaric Acid to Dimethylmaleic Acid

A new B(12)-coenzyme-dependent isomerization, catalyzed by extracts of a nicotinate-fermenting clostridium, results in the conversion of alpha-methyleneglutaric acid to dimethylmaleic acid. These two acids are intermediates in the multistep anaerobic process wherein nicotinate is converted, ultimately, to one mole each of propionate, acetate, carbon dioxide, and ammonia.Dimethylmaleic acid reacts in its anhydride form with 2,4-dinitrophenylhydrazine to form N-2',4'-dinitrophenyl-anilino-3,4-dimethylmaleimide. The characteristic reddish color exhibited by the latter derivative in alkaline solution serves as a convenient quantitative assay for dimethylmaleic acid. Comparison of the 2,4-dinitrophenylhydrazine derivatives of the product of the enzymic reaction and of synthetic dimethylmaleic anhydride showed them to be identical in every respect.     

Do physicians with diabetes have differences in dialysis use and survival than other patients with diabetes

Aims

To assess whether the increased knowledge and resources available to physicians led to differences in dialysis and survival rates between physicians and non-physician patients with diabetes.

Methods

All newly diagnosed (1997–2009) type 2 diabetes patients aged ≥35 years from the National Health Insurance Program of Taiwan database were included. After propensity score matching (1:10), we estimated the relative risk of dialysis and death using Cox proportional hazards model adjusted for demographic characteristics and comorbidities.

Results

Physicians with diabetes were more likely to start dialysis than general patients, with a 48% increased hazard risk (HR) (P = 0.006). Physicians with diabetes had significantly lower risk of death (HR: 0.88; P = 0.025). However, those requiring dialysis had a non-significant increased risk of death (HR: 1.19). There was an increased HR for death in older physicians (HR: 1.81; P < 0.001) and those with cancer or catastrophic illness. The HR of dialysis (7.89; P < 0.0001) increased dramatically with increasing Charlson Comorbidity Index scores.

Conclusions

Physicians with DM survived longer than other patients with diabetes, likely benefiting from their professional resources in disease control and prevention. Nonetheless, they displayed no advantage from their medical backgrounds compared with the general patients if they developed end stage renal disease.     

Dynamic PET/CT imaging of 18F-(2S, 4R)4-fluoroglutamine in healthy volunteers and oncological patients

European Journal of Nuclear Medicine and Molecular Imaging - The purpose of this study was to compare dynamic 18F-FGln PET/CT images of healthy subjects and cancer patients and explore the best...     

Childhood insulinoma masquerading as seizure disorder

A 9 year old girl presented with seizures, weight gain and early morning behavioural changes. She had been commenced on anticonvulsants and was subsequently diagnosed with hyperinsulinaemic hypoglycaemia. This case demonstrates the importance of blood glucose monitoring in children presenting with new‐onset seizures and/or with early morning or fasting behavioural changes, the challenges in localizing the lesion, as well as the difficulties in achieving normoglycaemia prior to, and immediately following, surgery.     

Distinct patterns of ALDH1A1 expression predict metastasis and poor outcome of colorectal carcinoma

Purpose: Aldehyde dehydrogenase 1A1 (ALDH1A1) has been proposed as a candidate biomarker for colorectal carcinoma (CRC). However, the heterogeneity of its expression makes it difficult to predict the outcome of CRC. The aim of this study was to evaluate the diagnostic and prognostic value of this molecule in CRC. Methods and Results: In this study, we examined ALDH1A1 expression by immunohistochemistry including 406 cases of primary CRC with corresponding adjacent mucosa, with confirmation of real-time PCR and Western blotting. We found that the expression patterns of ALDH1A1 were heterogeneous in the CRC and corresponding adjacent tissues. We defined the ratio of ALDH1A1 level in adjacent mucosa to that in tumor tissues as R_A/C and found that the capabilities of tumor invasion and metastasis in the tumors with R_A/C < 1 were significantly higher than those with R_A/C ≥ 1. Follow-up data showed the worse prognoses in the CRC patients with R_A/C < 1. For understanding the underlying mechanism, the localization of β-catenin was detected in the CRC tissues with different patterns of ALDH1A1 expression from 221 patients and β-catenin was found preferentially expressed in cell nuclei of the tumors with R_A/C < 1 and ALDH1A1^high expression of HT29 cell line, indicating that nuclear translocation of β-catenin might contribute to the increased potentials of invasion and metastasis. Conclusion: Our results indicate that R_A/C is a novel biomarker to reflect the distinct expression patterns of ALDH1A1 for predicting metastasis and prognosis of CRC.     

Evaluation of serum anti-mullerian hormone as a biomarker of early ovarian aging in young women undergoing IVF/ICSI cycle

Objective: To determine whether or not the level of serum anti-Müllerian hormone (AMH) is related to early ovarian aging in young women (< 35 years of age) undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Design: Retrospective cohort study. Setting: An IVF laboratory in a university hospital in Taiwan. Patient (s): 70 young women (< 35 years of age) with low level of serum AMH (< 2 ng/ml) and 104 young women with level of serum AMH (≥ 2 ng/ml) who underwent IVF/ICSI cycles between January 2011 and November 2012 were enrolled. Intervention (s): None. Main outcome measure (s): Number of oocytes, fertilization rate, embryo quality, cycle cancellation rate, clinical pregnancy/abortion rate, and perinatal/infant outcomes. Results: The clinical pregnancy rate per transfer was favorable (low AMH group vs. normal AMH group [47.2% and 47.9%]) for women < 35 years of age, including women with a low serum AMH. Similarly, the live birth rate per transfer (low AMH group vs. normal AMH group [37.7% and 35.4%]) and perinatal outcomes were also comparable between the two groups. A significantly higher cycle cancellation was noted in the low AMH group than the normal AMH group (24.2% vs. 7.6%). Conclusion: Although early ovarian aging should be taken into consideration for young and infertile women with low AMH level than expected, our results suggest that low serum AMH level may suggest early ovarian aging in accelerated oocyte loss only, but may not fully represent “early ovarian aging” based on the favorable outcomes of pregnancy.     

An assessment of drug information sheets for diabetic patients: only active involvement by patients is helpful

Insulin/sulphonylurea-treated diabetics attending a busy university diabetic clinic were studied to determine whether issuing drug information sheets and/or age influenced understanding and behaviour regarding their disease and its treatment, especially with respect to avoiding hypoglycaemia. Patients were each asked 10 basic questions (each correct answer scoring 1), stratified by age (20 were less than or equal to 45 years and 91 greater than 45 years). According to a single-blind randomised protocol, they were issued or not issued with drug information sheets (providing information to correctly answer all 10 questions). After 2-3 months, 107 (88 aged greater than 45 years) were retested and asked whether they recalled an information sheet, read it themselves or had it read to them. Whether or not patients received sheets, corresponding mean aggregate scores were very similar in both age groups and there was no correlation with age. Second test scores yielded clinically and statistically significant increments in both the sheet and no sheet groups, respective mean aggregate scores increasing from 4.48 to 5.80 and 5.14 to 6.27 (P less than 0.001). Among patients issued with sheets, 32 who recalled reading them achieved the greatest improvement in mean scores (4.53 to 6.16, P less than 0.001). Active interaction/communication (participation in first test, recall and reading of information sheet) had a favourable educational impact irrespective of age, but merely issuing drug information sheets had no benefit.     

Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells

Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhi-bitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL–, and induce apoptosis of BCR-ABL–expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL– and mutant FLT3-expressing cells both in vitro and in vivo.     

Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma

The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1-dependent migration was regulated by the P13K and ERK/ MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.