Ferritin/alanine aminotransferase ratio as a possible marker for predicting the prognosis of acute liver injury

Background and Aims: Serum levels of ferritin and heme oxygenase (HO)‐1 are both markers of macrophage activation. We evaluated simple markers for predicting the prognosis of severe acute liver injury in which macrophage activation plays an important role. Methods: Subjects comprised 114 patients with acute liver injury, admitted to the liver unit of Nagasaki Medical Center between January 2001 and September 2010. Subjects included 11 patients with fulminant hepatic failure (FHF), 82 patients with ordinary acute hepatitis (AH), and 21 patients with severe‐form AH (AHS). We determined serum levels of ferritin, HO‐1 and other biochemical makers, and analyzed relationships between clinical outcomes of patients and each of these parameters alone and in combination. Results: Median serum ferritin levels were significantly higher in FHF (25 900 ng/mL) and AHS (3060 ng/mL) than in AH (700 ng/mL; P < 0.01 each). Median HO‐1 levels were also significantly higher in FHF (123 ng/mL) and AHS (51 ng/mL) than in AH (19 ng/mL; P < 0.01 each). Similarly, median ferritin/alanine aminotransferase (F/A) ratio was significantly higher in FHF (6.7) than in AHS (1.6, P < 0.05) or AH (0.5, P < 0.01). Among the 11 FHF patients, three recovered, seven died and one underwent liver transplantation. The ability of F/A ratio to distinguish non‐survivors from survivors was analyzed using receiver operating characteristics curves. A cut‐off level of 3.12 provided high sensitivity (87.5%) and specificity (81.2%). Conclusion: These results suggest that F/A ratio offer a quick and simple marker for predicting the prognosis of acute liver injury.     

Protective effect of tetramethylpyrazine and salvianolic acid B on apoptosis of rat cerebral microvascular endothelial cell under high shear stress

Apoptosis induced by high shear stress has been reported for the dysfunction of various vascular endothelial cells. We investigated the protective effects of tetramethylpyrazine (TMP) and salvianolic acid B (SAB) from Chinese medicine on the shear-induced early and late stages of apoptosis in cultured rat cerebral microvascular endothelial cells (rCMECs) under pathological high shear stress. Near-confluent cultures of rCMECs were pretreated with TMP or SAB and their combinational dosages, and exposed to high shear stress generated by a rheometer. Apoptotic death rate of rCMECs was assessed by immunofluorescence microscopy of Annexin V-FITC and propidium iodide (PI). We found that early and late stage apoptosis occurred at 3.0 Pa for a short duration of 450 sec but did not occur at 1.5 Pa. SAB inhibited the cells from apoptosis at concentrations from 10 microM to 20 microM in a dose-dependent manner, while effect of TMP at 0.37 mM and 0.73 mM did not significantly differ. Moreover, the combined use of TMP and SAB had synergistic anti-apoptotic effects (P<0.01). The results indicate that the anti-apoptotic effect of TMP and SAB on rheologically induced endothelial injury is likely involved in their efficacy.     

Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin

Since a variety of cell intrinsic and extrinsic molecular abnormalities cooperatively promote tumor formation in multiple myeloma (MM), therapeutic approaches that concomitantly target more than one molecule are increasingly attractive. We herein demonstrate the anti-myeloma effect of a cephalotaxus alkaloid, homoharringtonine (HHT), an inhibitor of protein synthesis, through the induction of apoptosis. HHT significantly reduced Mcl-1, a crucial protein involved in myeloma cell survival, in all three myeloma cell lines examined, whereas certain BH3-only proteins, such as Bim, Bik, and Puma, remained unchanged following HHT treatment, and their expression levels depended on the cell type. HHT also reduced the levels of c-FLIP(L/S), activated caspase-8, and induced active truncated-Bid. Thus, HHT-induced apoptosis appears to be mediated via both intrinsic and extrinsic apoptosis pathways, and the resultant imbalance between BH3-only proteins and Mcl-1 may be pivotal for apoptosis by HHT. In addition, HHT treatment resulted in reduced levels of beta-catenin and XIAP proteins, which also contribute to disease progression and resistance to chemotherapy in MM. In combination, HHT enhanced the effects of melphalan, bortezomib, and ABT-737. These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules.     

Reconstruction of Obliterated Vesicourethral Junction: Use of the Bulbar Urethra as a Continent Valve

Reconstruction of the obliterated vesicourethral junction is both complex and difficult. Here, we report an innovative method using a mobilized bulbar urethra as a continent valve. Three patients with major problems at the vesicourethral junction underwent continent valve reconstruction. In cases 1 and 2, in which there were problems at the anastomosing site after radical prostatectomy, the bladder wall was closed, wedge resection of the midline pubic bone was performed, and a fully mobilized bulbar urethra was implanted submucosally into the anterior bladder wall. In case 2, augmentation cystoplasty using an ileal segment was required due to the small capacity of the bladder. In case 3, in which there was posterior urethra disruption associated with pelvic fracture, the bulbar urethra was implanted into the bladder wall in the same manner as in cases 1 and 2 without pubectomy. The postoperative follow‐up periods were 48, 36, and 12 months, respectively. In all patients, urinary management was achieved by self‐catheterization postoperatively, and the patients were satisfied with their status. This newly devised continent valve construction using a bulbar urethra is effective for reconstruction of the obliterated vesicourethral junction, which markedly improves patients' quality of life.     

Effect of intravascular ultrasound-guided adjuvant high-pressure non-compliant balloon post-dilation after drug-eluting stent implantation

Drug-eluting stent (DES) expansion characteristics after aggressive high-pressure post-dilation using a non-compliant (NC) balloon have not been fully investigated. We evaluated 58 patients with native coronary lesions treated with DESs [24 paclitaxel eluting stents (PES) and 34 sirolimus-eluting stents (SES)]. After post-dilation (12–14 atm) using a stent-mounted semi-compliant balloon to reduce stent edge injury, adjuvant high-pressure post-dilation using NC balloon was performed within the stents. Stent size, stent length, and NC balloon size were selected based on preinterventional intravascular ultrasound (IVUS) assessment. Stent underexpansion was defined according to criteria of the Multicenter Ultrasound Stenting in Coronaries (MUSIC) study as a minimal stent cross-sectional area <90% of the average reference lumen area. Resultant endpoint was to obtain optimal stent expansion. Serial changes of stent expansion and stent symmetry were calculated in each group. After stent-mounted semi-compliant balloon post-dilation, both stents could not achieve adequate percent stent expansion (PES 73 ± 18% vs. SES 67 ± 9%, p = 0.38). After high-pressure post-dilation using an NC balloon, percent stent expansion was 97 ± 14% in PES and 91 ± 13% in SES, respectively (p = 0.25). Axial stent symmetry indices also significantly improved in both groups. Although radial stent symmetry indices improved significantly in PES group, those in the SES group had no significant changes. Finally, frequency of stent underexpansion significantly reduced, 87–20% in PES and 92–15% in SES, respectively (p = 0.01) without any significant stent edge injury. DES expansion improved safely after adjuvant high-pressure post-dilation using an NC balloon under IVUS guidance.     

Chylomicronemia caused by lipoprotein lipase gene mutation related to a hyper-response of insulin secretion to glucose

A 39-year-old man with lipoprotein lipase (LPL) deficiency (height 177.7 cm, body weight 67 kg, and body mass index 21.2 kg/m2) showed severe hypertriglyceridemia (2,032 mg/dl). LPL activity and concentration were markedly low in postheparin plasma. LPL gene analysis revealed a homozygous mutation, Asp204 --> Glu in exon 5. Fasting plasma glucose (81 mg/dl) and insulin (2.7 microU/ml) levels were normal. Plasma glucose pattern during oral glucose (75 g) tolerance test was normal, however 30 minutes after glucose-loading the insulin secretion unexpectedly increased to 89.4 microU/ml. These data suggested that chylomicronemia might be related to a hyper-response of insulin secretion to glucose without obesity.     

Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia

Diamond-Blackfan anaemia (DBA) is a cancer-prone genetic disorder characterized by pure red-cell aplasia and associated physical deformities. The ribosomal protein S19 gene (RPS19) is the most frequently mutated gene in DBA (~25%). TP53-mediated cell cycle arrest and/or apoptosis in erythroid cells have been suggested to be major factors for DBA development, but it is not clear why mutations in the ubiquitously expressed RPS19 gene specifically affect erythropoiesis. Previously, we showed that RPS19 deficiency in zebrafish recapitulates the erythropoietic and developmental phenotypes of DBA, including defective erythropoiesis with severe anaemia. In this study, we analysed the simultaneous loss-of-function of RPS19 and Tp53 in zebrafish to investigate the role of Tp53 in the erythroid and morphological defects associated with RPS19 deficiency. Co-inhibition of Tp53 activity rescued the morphological abnormalities, but did not alleviate erythroid aplasia in RPS19-deficient zebrafish. In addition, knockdown of two other RP genes, rps3a and rpl36a, which result in severe morphological abnormalities but only mild erythroid defects, also elicited an activated Tp53 response. These results suggest that a Tp53-independent but RPS19-dependent pathway could be responsible for defective erythropoiesis in RPS19-deficient zebrafish.     

Effects of blood pressure and the renin‐angiotensin system on platelet activation in type 2 diabetes

Aims/Introduction: Platelet‐derived microparticles (PDMP) are released from the platelets either after activation or in response to physical stimulation in vivo. The present study examined the association between blood pressure and PDMP, and the effects of high‐dose angiotensin receptor blockers (ARB) on PDMP in patients with type 2 diabetes. Materials and Methods: The study subjects consisted of 28 type 2 diabetes patients with blood pressure ≥130/80 mmHg who were treated with valsartan (80 mg daily). The patients were randomly assigned to take either 80 mg of telmisartan (Tel group) or 160 mg of valsartan (Val group) and then were followed up for 24 weeks. Thereafter, the patients were switched to combination therapy (5 mg of amlodipine with 40 mg of telmisartan [Tel group] or 80 mg of valsartan [Val group]) for 12 weeks. Results: Although the ambulatory blood pressure did not change, the PDMP levels were significantly decreased from baseline to week 24 (high dose ARB). In contrast, combination therapy reduced both blood pressure and PDMP levels compared with the baseline. Although the PDMP level was significantly correlated with the morning BP elevation at baseline and week 36 (combination therapy), this same relationship was not found at week 24. There were no significant differences in the blood pressure and PDMP levels between the two groups. Conclusions: Patients with morning hypertension might be at risk for cardiovascular diseases. High‐dose renin‐angiotensin system inhibition and blood pressure control are both considered to reduce cardiovascular events in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00048.x, 2010)     

Potentially Reversible Resident Factors Associated with Rejection of Care Behaviors

OBJECTIVES: To identify the potentially modifiable resident‐level factors associated with rejection of care in nursing home (NH) residents. DESIGN: Secondary analysis of a 3.0 national field test to revise the Minimum Data Set (MDS). SETTING: Seventy‐one NHs in eight states. PARTICIPANTS: Three thousand two hundred thirty NH residents scheduled for MDS assessments from September 2006 through February 2007. MEASUREMENTS: The potentially mutable characteristics assessed were mood (Patient Health Questionnaire‐9), delirium (Confusion Assessment Method), delusions, hallucinations or illusions, hearing impairment, vision impairment, pain severity, and infection diagnoses. Characteristics considered as covariates were cognition, communication abilities, and impairment in activities of daily living. RESULTS: Of 3,230 residents assessed, 312 (9.7%) had demonstrated rejection of care in the preceding 5 days. In multiple regression analysis adjusted for covariates, rejection of care was associated with delusions (odds ratio (OR)=3.9; 95% confidence interval (CI)=2.5–6.0), delirium (OR=1.8, 95% CI=1.3–2.4), minor (OR=2.1, 95% CI=1.5–2.8) and major (OR=2.3, 95% CI=1.5–3.4) depression, and severe to horrible pain (OR=1.6, 95% CI=1.1–2.3). Infection diagnoses were not significant in bivariate analysis. Hallucinations or illusions, mild to moderate pain, and hearing and vision impairment were not significant in multiple regression analysis. CONCLUSION: In this population, delirium, delusions, depression, and severe pain were associated with rejection of care, suggesting that some care rejection behaviors may resolve with appropriate interventions for the identified target conditions if the associations observed are causal.