Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal-dominant familial Parkinson's disease (FPD). The variable pathological features of LRRK2-linked FPD include Lewy bodies, degeneration of anterior horn cells associated with axonal spheroids, neurofibrillary tangles (NFTs) and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusion bodies. Furthermore, abnormal hyperphosphorylation of microtubule associated protein tau, in part generated by catalysis of protein kinases, has been reported to be involved in progressive neurodegeneration in a number of diseases, including FPD. Thus, we examined six patients carrying the LRRK2 I2020T mutation, a pathogenic mutation associated with PARK8, and found abnormal tau phosphorylation depositions in the brainstem. Additionally, we found LRRK2 I2020T enhanced tau phosphorylation in cultured cells co-expressing LRRK2-I2020T and 3 or 4-repeated tau. This is the first report describing the relationship between hyperphosphorylation of tau and LRRK2 I2020T.

BACKGROUND Recurrence following liver transplantation for hepatitis C virus (HCV), which is universal, affects long-term outcomes. Treatment with interferon (IFN) and ribavirin (RBV), the only widely available options at this time, have been faced with low tolerability and overall unsatisfactory results in deceased donor liver transplantation (DDLT). However, its place after living donor liver transplantation (LDLT) remains a matter of debate. Since most LDLT cases are performed in a planned manner at a lower Model for End-stage Liver Disease (MELD) score compared to DDLT, we have aggressively applied preemptive INF/RBV in our series. PATIENTS AND METHODS We studied 122 adult recipients who underwent LDLT for HCV-related end-stage liver disease. The preemptive IFN/RBV protocol initiated treatment promptly after improvement in the patient's general condition with a low-dose IFN alpha2b and RBV (400 mg/d) followed by a gradual increase in the INFalpha2b dosage. Finally, we applied pegylated IFN (1.5 ug/kg/wk) and RBV (800 mg/d). The treatment was continued for 12 months after serum HCV-RNA became negative, which was defined as the end-of-treatment response (ETR). The response was considered to be a sustained viral response (SVR) if there were negative serologic results without antiviral treatment for another 6 months. Splenectomy was performed at the time of LDLT to improve tolerability to INF/RBV. The median age of the patients was 55 yrs (range = 23-66), with male dominance (87 males and 35 females). Median MELD score was 14 (range = 6-48). The series included 72 patients with hepatocellular carcinomas, and six with HIV coinfections. In 98 cases, HCV genotype was 1b. RESULTS Overall survival at 5 years was 79%. Cumulative response rates under the protocol were ETR 56% and SVR 44% at 5 years. CONCLUSIONS Preemptive IFN/RBV therapy after LDLT for HCV is feasible with acceptable outcomes.

We report two cases of intermittent Wolff-Parkinson-White (WPW) syndrome. In one patient, early repolarization (ER) was masked during preexcitation whereas in the other, J wave-like notches were observed in the right precordial leads only during preexcitation. The clinical significance of ER is not apparent in WPW syndrome but some possible mechanisms are discussed.(PACE 2012; 1-3).

Clonogenic multiple myeloma (MM) cells reportedly lacked expression of plasma cell marker CD138. It was also shown that CD19(+) clonotypic B cells can serve as MM progenitor cells in some patients. However, it is unclear whether CD138-negative clonogenic MM plasma cells are identical to clonotypic CD19(+) B cells. We found that in vitro MM colony-forming cells were enriched in CD138(-)CD19(-)CD38(++) plasma cells, while CD19(+) B cells never formed MM colonies in 16 samples examined in this study. We next used the SCID-rab model, which enables engraftment of human MM in vivo. CD138(-)CD19(-)CD38(++) plasma cells engrafted in this model rapidly propagated MM in 3 out of 9 cases, while no engraftment of CD19(+) B cells was detected. In 4 out of 9 cases, CD138(+) plasma cells propagated MM, although more slowly than CD138(-) cells. Finally, we transplanted CD19(+) B cells from 13 MM patients into NOD/SCID IL2Rγc(-/-) mice, but MM did not develop. These results suggest that at least in some MM patients CD138-negative clonogenic cells are plasma cells rather than B cells, and that MM plasma cells including CD138(-) and CD138(+) cells have the potential to propagate MM clones in vivo in the absence of CD19(+) B cells.Leukemia accepted article preview online, 20 March 2012; doi:10.1038/leu.2012.80.

Duodenal adenocarcinoma is a relatively rare malignancy and pancreaticoduodenectomy would be a standard procedure to achieve curative resection. We report a case of resection of the 2nd portion of the duodenum with nodal dissection preserving the pancreas. The patient was a 75-year-old man with right-sided paresis suffering from early cancer in the 2nd portion of the duodenum. Despite 3 times of endoscopic mucosal resections, mucosal local recurrence was found. The depth of the tumour involvement continued to be limited within the mucosal layer. We performed segmental duodenal resection with nodal dissection sacrificing the minor papilla, while preserving the pancreas and the major papilla. The pathological diagnosis was primary intramucosal adenocarcinoma; the surgical margin was negative for cancer and there was no nodal metastasis. This procedure can be an alternative to pancreaticoduodenectomy in patients with earlystage adenocarcinoma in the 2nd portion of the duodenum when the major papilla can be spared, especially in high-risk patients.

BACKGROUND Due to the organ shortage, many patients die without transplantation, even before completing an evaluation for candidacy. We analyzed outcomes after patient referral and factors associated with mortality both before and after listing for cadaveric donor liver transplantation. METHODS We analyzed 132 consecutive patients who were evaluated for candidacy for cadaveric donor liver transplantation between 2003 and 2010. RESULTS The study included 69 men and 63 women of median age 49 years (range, 1-65). Etiologies of diseases were acute hepatic failure (n = 19), liver cirrhosis due to hepatitis B or C (n = 36), primary biliary cirrhosis (n = 19), nonviral cirrhosis (n = 14), hepatocellular carcinoma (n = 13), or other causes (n = 31). After evaluation for candidacy, we listed 68 (52%), subjects whereas 24 (18%) died before listing. Factors affecting death before listing were the levels of albumin (P <.001), bilirubin (P <.001), sodium (P <.001), international normalized ratio (INR; P <.001), Model for End-stage Liver Disease (MELD) score (P <.001), MELD-Na score (P <.001), and Child-Pugh-Turcotte (CPT) score (P <.001). Based on multivariate Cox regression analysis, MELD score (hazard ratio [HR] 1.201, P =.017), MELD-Na score (HR 1.244, P =.014), CPT score (HR 1.468, P =.033), and INR (HR 0.491, P =.027) were independently associated with death before listing. Among 68 listed candidates, 11 (16%) underwent transplantation, whereas 29 (43%) died without transplantation. Based on multivariate Cox regression analysis, MELD score (HR 1.102, P =.001), MELD-Na score (HR 1.128, P =.001), and CPT score (HR 1.282, P =.038) independently predicted wait-list mortality. All 11 patients who underwent cadaveric liver transplantation were alive at 29 months (range, 1-55) after transplantation. CONCLUSIONS Patients with a higher MELD, higher MELD-Na, and higher CPT score at referral were at greater risk for death without transplantation, especially before listing. Evaluation for transplantation candidacy is a time-consuming process. Therefore, earlier referral is mandatory to achieve successful listing for transplantation.

Activation of the forkhead box transcription factor FoxO is suggested to be involved in dopaminergic (DA) neurodegeneration in a Drosophila model of Parkinson's disease (PD), in which a PD gene product LRRK2 activates FoxO through phosphorylation. In the current study that combines Drosophila genetics and biochemical analysis, we show that cyclic guanosine monophosphate (cGMP)-dependent kinase II (cGKII) also phosphorylates FoxO at the same residue as LRRK2, and Drosophila orthologues of cGKII and LRRK2, DG2/For and dLRRK, respectively, enhance the neurotoxic activity of FoxO in an additive manner. Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2. A Drosophila FoxO mutant resistant to phosphorylation by DG2 and dLRRK (dFoxO S259A corresponding to human FoxO1 S319A) suppressed the neurotoxicity and improved motor dysfunction caused by co-expression of FoxO and DG2. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) also increased FoxO's activity, whereas the administration of a NOS inhibitor L-NAME suppressed the loss of DA neurons in aged flies co-expressing FoxO and DG2. These results strongly suggest that the NO-FoxO axis contributes to DA neurodegeneration in LRRK2-linked PD.

What is known and Objectives:  Ropinirole hydrochloride, a dopamine receptor agonist with a non-ergot alkaloid structure, is highly selective for the dopamine D(2)/D(3) receptors. This study was conducted to evaluate the steady-state pharmacokinetics, safety and efficacy after repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in the absence of L-dopa preparations in Japanese patients with Parkinson's disease (PD). Methods:  This was a multicenter, open-label, uncontrolled study. The total duration of participation in the study ranged from 56 to 63 weeks. In the study, the plasma concentrations of ropinirole, its major metabolite SK&F104557 (N-depropyl ropinirole) and another metabolite SK&F89124 (ropinirole hydroxylated at the seventh position of the indole ring) were assessed. Safety based on adverse events, haematology, biochemistry, urinalysis and electrocardiography (ECG)(standard 12-lead ECG) were evaluated, and vital signs (blood pressure/pulse rate) were measured. Efficacy based on the Japanese version of Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (motor) and II [activities of daily living (ADL)] as well as tolerability was evaluated. Results:  After repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with PD, ropinirole, SK&F104557 and low levels of SK&F89124 were detected in plasma. The trough concentrations of ropinirole and the two metabolites increased in proportion to the dose when ropinirole hydrochloride prolonged-release tablets were administered at doses ranging from 2 to 16 mg/day. The plasma exposure to ropinirole and its two metabolites after intake of normal diet was comparable to that in the fasting state. The most common adverse events (10% or more) were somnolence, nausea, constipation, hallucination and nasopharyngitis. Most adverse events were mild or moderate in severity, and with no death. During the treatment period, serious adverse events were reported in five patients. Efficacy analysis (LOCF) at the final endpoint up to week 16 demonstrated a mean (SD) change from baseline in the Japanese UPDRS III (motor) and II (ADL) scores of -11·3 (8·21) and -3·9 (3·22), respectively, and thereafter remained at similar levels until week 52. What is new and Conclusions:  After administration of prolonged-release tablets of ropinirole hydrochloride in the absence of L-dopa preparations in Japanese patients with PD, the plasma pharmacokinetics of ropinirole and its metabolites was linear and not affected by food. Compared with the immediate-release (IR) tablet, the prolonged-release tablet can be administered to Japanese patients with PD at a reduced daily dose frequency and adjusted to the maintenance dose after fewer dose changes with a smaller diurnal variation in the plasma ropinirole concentration.

Synchrotron x-ray diffraction experiment shows that the metal-insulator transition occurring in a ferromagnetic state of a hollandite K_{2}Cr_{8}O_{16} is accompanied by a structural distortion from the tetragonal I4/m to monoclinic P112_{1}/a phase with a sqrt[2]×sqrt[2]×1 supercell. Detailed electronic structure calculations demonstrate that the metal-insulator transition is caused by a Peierls instability in the quasi-one-dimensional column structure made of four coupled Cr-O chains running in the c direction, leading to the formation of tetramers of Cr ions below the transition temperature. This provides a rare example of the Peierls transition of fully spin-polarized electron systems.