Hypercholesterolemia as a part of chronic GVHD after allogeneic stem cell transplantation

A 45-year-old female with acute myelogenous leukemia (AML-M6) received an allogeneic stem cell transplantation from an HLA-identical sibling donor in June 2002. Prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine (CsA) and short-term methotrexate. Acute GVHD did not occur and CsA was discontinued on day 145 after transplantation. However, soon thereafter she suffered from conjunctivitis, stomatitis and liver dysfunction with hypercholesterolemia and was diagnosed as having chronic GVHD. The liver dysfunction and hypercholesterolemia failed to improve despite the administration of CsA and prednisolone. Atrovastatin was not effective and immunosuppressive therapy for two months including ursodeoxycholic acid finally improved the jaundice and hypercholesterolemia. Although lipid metabolism analysis in this case disclosed the same findings as in other intrahepatic cholestatic liver diseases, the results show that the improvement of hypercholesterolemia in chronic GVHD needs the same treatment as chronic GVHD.     

Folate receptors targeted to clathrin-coated pits cannot regulate vitamin uptake.

Potocytosis is an endocytic process that is specialized for the internalization of small molecules. Recent studies on the uptake of 5-methyltetrahydrofolate by the folate receptor have suggested that the glycosyl-phosphatidylinositol anchor on this protein causes it to cluster and be internalized by caveolae instead of coated pits. To test this hypothesis directly, we have constructed a chimeric folate receptor that has the glycosyl-phosphatidylinositol anchor replaced with the transmembrane domain and cytoplasmic tail of the low density lipoprotein receptor. The cells with wild-type receptors delivered 5-methyltetrahydrofolate to the cytoplasm more rapidly than did cells expressing the chimeric receptor. This suggests that efficient delivery to the cytoplasm depends on caveolae. In sharp contrast to cells with wild-type folate receptors, cells internalizing folate by clathrin-coated pits were unable to decrease vitamin uptake when they were either folate replete or confluent.     

Two patients treated with pegylated interferon/ribavirin/telaprevir triple therapy for recurrent hepatitis C after living donor liver transplantation

It is difficult to use protease inhibitors in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) due to interaction with immunosuppressive drugs. We report our experience with two patients treated with telaprevir (TVR) combined with pegylated interferon/ribavirin (PEG IFN/RBV) for recurrent HCV genotype 1 infection after LT. The first was a 63‐year‐old man with HCV‐related liver cirrhosis, who failed to respond to IFN‐β plus RBV after LT. Treatment was switched to PEG IFN‐α‐2b plus RBV and TVR was started. The donor had TT genotype of interleukin (IL)‐28 single nucleotide polymorphisms (SNP) (rs8099917). The recipient had TT genotype of IL‐28 SNP (rs8099917). Completion of 12‐week triple therapy was followed by PEG IFN‐α‐2b plus RBV for 36 weeks. Finally, he had sustained viral response. The second was a 70‐year‐old woman with HCV‐related liver cirrhosis and hepatocellular carcinoma. She failed to respond to PEG IFN‐α‐2b plus RBV after LT, and was subsequently switched to PEG IFN‐α‐2b/RBV/TVR. Genotype analysis showed TG genotype of IL‐28 SNP for the donor, and TT genotype of IL‐28 SNP for the recipient. Serum HCV RNA titer decreased below the detection limit at 5 weeks. However, triple therapy was withdrawn at 11 weeks due to general fatigue, which resulted in HCV RNA rebound 4 weeks later. Both patients were treated with cyclosporin, starting with a small dose to avoid interactions with TVR. TVR is a potentially suitable agent for LT recipients who do not respond to PEG IFN‐α‐2b plus RBV after LT.     

Diurnal variation of carbohydrate insulin ratio in adult type 1 diabetic patients treated with continuous subcutaneous insulin infusion

To estimate the carbohydrate‐to‐insulin ratio (CIR), a formula dividing a constant, usually 300–500, by the total daily dose (TDD) of insulin, is widely utilized. An appropriate CIR varies for each meal of the day, however. Here, we investigate diurnal variation of CIR in hospitalized Japanese type 1 diabetic patients treated with continuous subcutaneous insulin infusion. After optimization of the insulin dose, TDD and total basal insulin dose (TBD) were 34.9 ± 10.2 and 9.3 ± 2.8 units, respectively, with a percentage of TBD to TDD of 27.3 ± 6.0%. The products of CIR and TDD at breakfast, lunch and dinner were 311 ± 63, 530 ± 161, and 396 ± 63, respectively, suggesting that in the formula estimating CIR using TDD, the constant should vary for each meal of the day, and that 300, 500, and 400 are appropriate for breakfast, lunch, and dinner, respectively.     

Evolutionary Anatomy and Phyletic Implication of the Extrinsic Cardiac Nervous System in the Philippine Tarsier (Tarsius syrichta,Primates) in Comparisons With Strepsirrhines and New World Monkeys

To provide information on evolutionary morphological differences and similarities between Tarsiformes (tarsiers) and other primates (Strepsirrhini and Platyrrhini), we examined the previously undescribed extrinsic cardiac nervous system (ECNS) and surrounding structures in three Philippine tarsiers (Tarsius syrichta). We found that the complicated ECNS morphology shows little variation in contrast to significant anatomical diversity of the surrounding somatic structures in tarsiers as reported in our previous primate studies. Further, our comparative morphological data on the ECNS show the following aspects of evolutionary anatomical significance; (1) the traits of the general relationship between the superior cervical ganglion and the spinal nerves are common to the Tarsii and Strepsirrhini, (2) the traits of the general composition of the cervicothoracic ganglion, its communicating branches to spinal nerves, and its cardiac nerve are common to the Tarsii and Platyrrhini, and (3) the traits of the general relationship between the middle cervical ganglion and the spinal nerves and its cardiac nerve are common among Strepsirrhini, Tarsii, and Platyrrhini. Therefore, the general anatomical characteristics of the ECNS in tarsiers retain a primitive state for some traits and exhibit a derived state for others. These characteristics of the ECNS also reflect an evolutionary history without the modification and specialization as seen in the surrounding somatic structures. It may play a key role in unifying future studies on molecular phylogeny and updating evolutionary anatomical information. Anat Rec, 296:798–806, 2013. © 2013 Wiley Periodicals, Inc.     

Modified Glasgow prognostic score in patients with incurable stage IV colorectal cancer

Background

The modified Glasgow prognostic score is an inflammation-based prognostic score. This study examined whether this score, measured before surgical procedures, could predict postoperative cancer-specific survival.

Methods

We retrospectively studied 79 colorectal cancer patients who underwent a surgical procedure for incurable stage IV disease. The modified Glasgow prognostic score (0 to 2) comprises C-reactive protein (≤10 vs >10 mg/L) and albumin (<35 vs ≥35 g/L) measurements.

Results

In terms of overall survival, univariate analysis revealed significant differences in the status of lung metastasis, peritoneal dissemination, distant metastasis, hemoglobin, C-reactive protein, albumin, tumor resection, adjuvant chemotherapy, and modified Glasgow prognostic score. Multivariate analysis revealed that hemoglobin (P = .019), adjuvant chemotherapy (P = .002), and modified Glasgow prognostic score (0 and 1, low; 2, high) (P = .0001) were significant predictive factors for postoperative mortality.

Conclusions

The modified Glasgow prognostic score is simple to obtain and useful in predicting survival in incurable stage IV colorectal cancer patients undergoing surgery.     

Plasma endoglin as a marker to predict cardiovascular events in patients with chronic coronary artery diseases

Recent clinical studies have revealed that the expression of endoglin, an accessory protein for the TGF-β receptor, is increased in patients with atherosclerotic diseases. The plasma endoglin level is thought to represent endothelial activation, inflammation, and senescence. To clarify the significance of plasma endoglin in chronic coronary artery disease. Human umbilical vein endothelial cells (HUVECs) were cultured to examine changes in soluble endoglin (s-endoglin) levels caused by atherogenic stimulation in vitro. We studied 318 patients with stable coronary artery disease who underwent a successful percutaneous coronary intervention (PCI). Patients with acute coronary syndrome were excluded. Major adverse cardiovascular events (MACE) were congestive heart failure, acute myocardial infarction, stroke, and sudden cardiac death. All patients were followed-up to examine MACE after the procedure. We confirmed that the levels of s-endoglin was increased in the culture medium of HUVECs by senescence, tumor necrosis factor-α and hydrogen peroxide. In a clinical study, mean follow-up period was 1055?±?612?days (49–2136?days) with 27 incidents of MACE (8.5%). We divided patients into three groups according to the plasma s-endoglin levels. Kaplan–Meier curves revealed that the highest endoglin group had a significantly higher MACE rate than the lowest endoglin group (log-rank test, p?=?0.009). A Cox proportional hazards model showed that chronic kidney disease, left ventricular ejection fraction and s-endoglin level were significant factors to predict MACE. Plasma endoglin could be a marker to predict cardiovascular events in patients with chronic coronary artery disease after PCI.