A 58-year-old immunocompetent man gradually developed loss of appetite, cognitive decline, gait disturbances, and personality changes over 4 months. Brain magnetic resonance imaging (MRI) revealed bilateral diffuse leukoencephalopathy without mass formation on admission. His condition progressively deteriorated, and we treated him with intravenous high-dose steroids. His symptoms improved rapidly, but exacerbated when therapy was withdrawn. A brain biopsy was performed, and the diagnosis of primary central nervous system lymphoma (PCNSL) was confirmed. He was successfully treated with high-dose methotrexate therapy. Although it is difficult to diagnose PCNSL without mass formation in the early stages, steroid responsiveness is important and brain biopsy is essential for the correct diagnosis of PCNSL.

It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (13)CO(2) excretion (T(max)) in the (13)C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (13)CO(2) excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (13)CO(2) excretion (T(max)) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ± 22.7 min and 42.5 ± 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (13)CO(2) excretion (T(max)) values without and with subthalamic deep brain stimulation after surgery were 44.0 ± 17.5 min and 30.0 ± 12.5 min (P < 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the (13)CO(2) excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (13)CO(2) excretion (T(max)) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Δghrelin) and changes in T(max) values (ΔT(max)) in the subthalamic deep brain stimulation trial after surgery (r = -0.20), and no association between changes in other characteristics and ΔT(max) post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease.

PURPOSE: We tested the validity of 3 recently proposed prognostic indexes for breast cancer patients with brain metastases (METs) treated radiosurgically. The 3 indexes are Diagnosis-Specific Graded Prognostic Assessment (DS-GPA), New Breast Cancer (NBC)-Recursive Partitioning Analysis (RPA), and our index, sub-classification of RPA class II patients into 3 sub-classes (RPA class II-a, II-b and II-c) based on Karnofsky performance status, tumor number, original tumor status, and non-brain METs. METHODS AND MATERIALS: This was an institutional review board-approved, retrospective cohort study using our database of 269 consecutive female breast cancer patients (mean age, 55 years; range, 26-86 years) who underwent Gamma Knife radiosurgery (GKRS) alone, without whole-brain radiation therapy, for brain METs during the 15-year period between 1996 and 2011. The Kaplan-Meier method was used to estimate the absolute risk of each event. RESULTS: Kaplan-Meier plots of our patient series showed statistically significant survival differences among patients stratified into 3, 4, or 5 groups based on the 3 systems (P<.001). However, the mean survival time (MST) differences between some pairs of groups failed to reach statistical significance with all 3 systems. Thus, we attempted to regrade our 269 breast cancer patients into 3 groups by modifying our aforementioned index along with the original RPA class I and III,(ie, RPA I+II-a, II-b, and II-c+III). There were statistically significant MST differences among these 3 groups without overlap of 95% confidence intervals (CIs) between any 2 pairs of groups: 18.4 (95% CI = 14.0-29.5) months in I+II-a, 9.2 in II-b (95% CI = 6.8-12.9, P<.001 vs I+II-a) and 5.0 in II-c+III (95% CI = 4.2-6.8, P<.001 vs II-b). CONCLUSIONS: As none of the new grading systems, DS-GPS, BC-RPA and our system, was applicable to our set of radiosurgically treated patients for comparing survivals after GKRS, we slightly modified our system for breast cancer patients.

BacD is an ATP-dependent dipeptide ligase responsible for the biosynthesis of l-alanyl-l-anticapsin, a precursor of an antibiotic produced by Bacillus spp. In contrast to the well-studied and phylogenetically related d-alanine:d-alanine ligase (Ddl), BacD synthesizes dipeptides using l-amino acids as substrates and has a low substrate specificity in vitro. The enzyme is of great interest because of its potential application in industrial protein engineering for the environmentally-friendly biological production of useful peptide compounds, such as physiologically active peptides, artificial sweeteners and antibiotics, but the determinants of its substrate specificity and its catalytic mechanism have not yet been established due to a lack of structural information. In this study, we report the crystal structure of BacD in complex with ADP and an intermediate analog, phosphorylated phosphinate l-alanyl-l-phenylalanine, refined to 2.5-Å resolution. The complex structure reveals that ADP and two magnesium ions bind in a manner similar to that of Ddl. However, the dipeptide orientation is reversed, and, concomitantly, the entrance to the amino acid binding cavity differs in position. Enzymatic characterization of two mutants, Y265F and S185A, demonstrates that these conserved residues are not catalytic residues at least in the reaction where l-phenylalanine is used as a substrate. On the basis of the biochemical and the structural data, we propose a reaction scheme and a catalytic mechanism for BacD.

Abstract: A telomere is a repetitive DNA structure at chromosomal ends that stabilizes the chromosome structure and prevents harmful end-to-end recombinations. The telomere length of somatic cells becomes shorter with aging because of the "end replication problem." This telomere shortening is accelerated by pathophysiological conditions including daily mental stress. Living with Parkinson's disease (PD) causes physical and mental stress; therefore, the authors hypothesized that the telomere length of somatic cells was shortened excessively in patients with PD. In order to detect PD-associated somatic telomeric alterations, the telomere length and subtelomeric methylation status of peripheral leukocytes of PD patients were assessed by Southern blotting, using methylation-sensitive and -insensitive isoschizomers. The results demonstrated that the peripheral leukocytes of Japanese female patients with PD bore fewer long telomeres and a proportional increase of hypomethylated subtelomeres in short telomeres in comparison with the healthy controls. This study indicates that with the neurodegeneration associated with PD, telomeric and subtelomeric structural alterations occur. These structural telomere altertions most likely occur secondary to the acceleration of aging-associated telomeric changes and the accelerated loss of cells bearing short telomeres.

Right on CueO: The O-centered structure of the trinuclear copper center in a multicopper oxidase (CueO) was shown to be an intermediate of the four-electron reduction of dioxygen. This structure was determined by in situ data collection of X-ray diffractions and copper K-edge spectra at low to high X-ray dose conditions.

Microembolization during percutaneous coronary intervention (PCI) causes minor myocardial injury, and a Doppler guidewire can detect embolic particles as high-intensity transient signals (HITS). The present study investigated the effect of microembolization during PCI on regional wall motion using a Doppler guidewire and myocardial strain analysis. We performed PCI to the left anterior descending coronary artery in 25 patients (18 men and 7 women, 68 ± 8 years old) with stable angina pectoris. Coronary flow spectrums were obtained with a Doppler guidewire to count the total number of HITS throughout the PCI procedures. On the days before and after PCI, we recorded echocardiography and measured the longitudinal peak systolic strain, peak strain rate, and early diastolic strain rate in the left anterior descending territory using a 2-dimensional speckle tracking method. PCI was successfully performed, and 10 ± 6 HITS (range 0 to 22, median 9) were recognized during PCI. The echocardiographic study showed no visible wall motion abnormalities in the left anterior descending territory either after or before PCI. In cases in which the total number of HITS was ≥10, the peak systolic strain, peak strain rate, and early diastolic strain rate worsened on the day after PCI compared with those on the day before PCI (p <0.01). The rates of change in peak systolic strain and early diastolic strain rate, defined as the ratios of those parameters after PCI to those before PCI, had modest to strong inverse correlations with the total number of HITS (R(2)= 0.35 and R(2)= 0.46, respectively). In conclusion, periprocedural microembolization during PCI reduces subclinical cardiac function in patients with stable angina pectoris.

PURPOSE: Although the recursive partitioning analysis (RPA) class is generally used for predicting survival periods of patients with brain metastases (METs), the majority of such patients are Class II and clinical factors vary quite widely within this category. This prompted us to divide RPA Class II patients into three subclasses. METHODS AND MATERIALS: This was a two-institution, institutional review board-approved, retrospective cohort study using two databases: the Mito series (2,000 consecutive patients, comprising 787 women and 1,213 men; mean age, 65 years [range, 19-96 years]) and the Chiba series (1,753 patients, comprising 673 female and 1,080 male patients; mean age, 65 years [range, 7-94 years]). Both patient series underwent Gamma Knife radiosurgery alone, without whole-brain radiotherapy, for brain METs during the same 10-year period, July 1998 through June 2008. The Cox proportional hazard model with a step-wise selection procedure was used for multivariate analysis. RESULTS: In the Mito series, four factors were identified as favoring longer survival: Karnofsky Performance Status (90% to 100% vs. 70% to 80%), tumor numbers (solitary vs. multiple), primary tumor status (controlled vs. not controlled), and non-brain METs (no vs. yes). This new index is the sum of scores (0 and 1) of these four factors: RPA Class II-a, score of 0 or 1; RPA Class II-b, score of 2; and RPA Class II-c, score of 3 or 4. Next, using the Chiba series, we tested whether our index is valid for a different patient group. This new system showed highly statistically significant differences among subclasses in both the Mito series and the Chiba series (p < 0.001 for all subclasses). In addition, this new index was confirmed to be applicable to Class II patients with four major primary tumor sites, that is, lung, breast, alimentary tract, and urogenital organs. CONCLUSIONS: Our new grading system should be considered when designing future clinical trials involving brain MET patients.

OBJECTIVE: We created software for patterning uroflowmetry (UFM) curves, and validated its utility. PATIENTS AND METHODS: The software patterns a given UFM curve upon four parameters: sex, voided volume, maximal flow rate, and amplitude of fluctuation. Using the software, 6 urologists from 4 institutes assessed 30 test curves. Further, 329 UFM curves obtained from children presenting to 3 institutes for daytime and/or nighttime wetting were assessed. Clinical presentation was divided into 3 groups: group A, daytime incontinence; group B, non-monosymptomatic nocturnal enuresis without daytime wetting; and group C, monosymptomatic nocturnal enuresis. RESULTS: Using the software, inter-rater agreement ranged from 0.85 to 1.00 (mean, 0.93 ± 0.04). It could pattern 310 out of 329 clinical curves. In each institute, the tower pattern was prevalent according to severity of daytime symptoms, although not significantly. The merged data showed that the percent tower pattern significantly correlated with presence of daytime symptoms (groups A, B, and C, 29.7%, 27.0%, and 16.3%, respectively; p < 0.05). No correlation with daytime symptoms was noted for fluctuated (staccato and interrupted) and plateau patterns. CONCLUSION: The software creates a common platform for evaluating pediatric UFM, enabling extraction of common and biased features of different cohorts, and their integration into one single cohort.

We performed x-ray crystallographic analyses of the 6-aminohexanoate oligomer hydrolase (NylC) from Agromyces sp. at 2.0 Å-resolution. This enzyme is a member of the N-terminal nucleophile (N-tn) hydrolase superfamily that is responsible for the degradation of the nylon-6 industry byproduct. We observed four identical heterodimers (27kDa+9kDa), which resulted from the autoprocessing of the precursor protein (36kDa) and which constitute the doughnut-shaped quaternary structure. The catalytic residue of NylC was identified as the N-terminal Thr267 of the 9kDa-subunit. Furthermore, each heterodimer is folded into a single domain, generating a stacked abba core structure. Amino acid mutations at subunit interfaces of the tetramer were observed to drastically alter the thermostability of the protein. In particular, four mutations (D122G/H130Y/D36A/E263Q) of wild-type NylC from Arthrobacter sp.(plasmid pOAD2-encoding enzyme), with a heat denaturation temperature of Tm=52°C, enhanced the protein thermostability by 36°C (Tm=88°C), whereas a single mutation (G111S or L137A) decreased the stability by approximately 10°C. We examined the enzymatic hydrolysis of nylon-6 by the thermostable NylC mutant. Argon-cluster secondary ion mass spectrometry analyses of the reaction products revealed that the major peak of nylon-6 (m/z 10,000-25,000) shifted to a smaller range, producing a new peak corresponding to m/z 1500-3000 after the enzyme treatment at 60°C. In addition, smaller fragments in the soluble fraction were successively hydrolyzed to dimers and monomers. Based on these data, we propose that NylC should be designated as nylon hydrolase (or nylonase). Three potential uses of NylC for industrial and environmental applications are also discussed.