bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spinal Muscular Atrophy: Present State
Authors: Schmalbruch Henning , Haase Georg 
Published: July 2010

Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease caused by homozygous deletions or mutations in the SMN1 gene on Chr.5q13. SMA spans from severe Werdnig‐Hoffmann disease (SMA 1) to relatively benign Kugelberg‐Welander disease (SMA 3). Onset before birth possibly aggravates the clinical course, because immature motoneurons do not show compensatory sprouting and collateral reinnervation, and motor units in SMA 1, in contrast to those in SMA 3, are not enlarged. Genetic evidence indicates that SMN2, a gene 99% identical to SMN1, can attenuate SMA severity: in patients, more SMN2 copies and higher SMN protein levels are correlated with milder SMA. There is evidence that SMN plays a role in motoneuron RNA metabolism, but it has also been linked to apoptosis.Several mouse models with motoneuron disease have been successfully treated with neurotrophic factors. None of these models is, however, homologous to SMA. Recently, genetic mouse models of SMA have been created by introducing human SMN2 transgenes into Smn knockout mice or by targeting the Smn gene knockout to neurons. These mice not only provide important insights into the pathogenesis of SMA but are also crucial for testing new therapeutic strategies. These include SMN gene transfer, molecules capable to up‐regulate SMN expression and trophic or antiapoptotic factors.
What is an Oligodendroglioma?
Authors: Burger Peter C. 
Published: July 2010

Editor's Note: With this issue, we begin a new series of articles entitled “Controversies in neuropathology.” These will represent brief position papers on controversial topics in our specialty. They are not intended to be review articles, rather will represent “position papers” on topical issues, with a relatively circumscribed and selective bibliography. Authors of these papers are encouraged to present and defend their own views on the subject in question. Most of these papers will be by invitation, but authors who would like to submit an article for this series are encouraged to contact the Brain Pathology editorial office. HVV
Endogenous Ciliary Neurotrophic Factor Protects GABAergic, But Not Cholinergic, Septohippocam pal Neurons Following Fimbria‐fornix Transection
Authors: Naumann Thomas , Schnell Oliver , Zhi Qixia , Kirsch Matthias , Schubert Klaus Oliver , Sendtner Michael , Hofmann Hans‐Dieter 
Published: July 2010

Application of neurotrophic proteins including ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), members of the family of gp130‐associated cytokines, can rescue CNS neurons from injury‐induced degeneration. However, it is not clear so far if these effects reflect a physiological function of the endogenous cytokines. Using fimbria‐fornix transection as a model, we examined whether responses of GABAergic and cholinergic septohippocampal neurons to axotomy are altered in mice lacking CNTF. In addition, we studied the cellular expression of CNTF, LIF and related cytokine receptor components in the septal complex following lesion.Degeneration of septohippocampal GABAergic neurons in the medial septum as indicated by the loss of parvalbumin‐immunoreactive neurons was accelerated and permanently enhanced in CNTF' mice as compared to wild‐type animals. Unexpectedly, the number of axotomized cholinergic MS neurons was significantly higher in CNTF‐deficient mice during the first 2 weeks postlesion. Both in wild‐type and in CNTF‐/‐ mutants, expression of mRNAfor the CNTF‐specific α‐subunit of the cytokine receptor complex was specifically upregulated in axotomized GABAergic septal neurons, whereas enhanced expression of the LIF‐binding β‐subunit was specifically observed in axotomized cholinergic neurons. Following lesion, CNTF expression in wild‐type mice was induced in activated astrocytes surrounding the axotomized neurons and at the lesion site. Expression of LIF mRNA was localized in the GABAergic and cholinergic septohippocampal neurons.These results strongly indicate that endogenous CNTF, supplied by reactive glia cells, acts as a neuroprotective factor for axotomized CNS neurons. In the septum, endogenous CNTF specifically supports lesioned GABAergic projection neurons, whereas LIF may play a similar role for the cholinergic counterparts.
APRIL 2004: WOMAN IN HER EARLY FIFTIES WITH A CERVICAL INTRASPINAL AND EXTRASPINAL MASSLESION
Authors: Hamilton Ronald L. , Kuchelmeister Klaus , Lotz Claudia , Schönmayr Robert , Schachenmayr Walter 
Published: July 2010

CASE OF THE MONTH: ABSTRACTApril 2004: A 53‐year‐old woman presented with a large club‐shaped intra‐ and extraspinal tumor of the C6 nerve root which had intradurally grown through the enlarged C5–6 neural foramen and focally infiltrated the dura mater. Microscopy revealed a melanin‐pigmented tumor with spindle‐shaped and epithelioid cells and scattered psammoma bodies, a so‐called psammomatous melanotic schwannoma (PMS). More than half of the patients with PMS have Carney complex, a genetically heterogeneous multiple neoplasia syndrome of autosomal‐dominant inheritance, which in our patient, however, could not be detected unequivocally. Prognosis of all melanotic schwannomas (MSs) is not good with local recurrences or metastases in over 40% of cases. In our case, frequent versicular nuclei with distinct nucleoli, occasional mitoses and apoptoses and increased focal MIB‐1 labeling indices prompted us to diagnose a malignant PMS. However, histologic criteria for malignancy in MSs are not clearly defined and there is no reliable histopathological indicator of malignant clinical behavior in MSs. Therefore, designation of “PMS with malignant histologic features” may be more appropriate. Since tumor recurrences and metastases im MSs may occur after more than 5 years, long‐term follow‐up of affected patients is required. One year after operation our patient showed no signs of tumor recurrence or metastases.
Gestational Hypoxia Induces White Matter Damage in Neonatal Rats: A New Model of Periventricular Leukomalacia
Authors: Baud Olivier , Daire Jean‐Luc , Dalmaz Yvette , Fontaine Romain H , Krueger Richard C. , Sebag Guy , Evrard Philippe , Gressens Pierre , Verney Catherine 
Published: July 2010

In the premature infant, periventricular leukomalacia, usually related to hypoxic‐ischemic white matter damage, is the main cause of neurological impairment. We hypothesized that protracted prenatal hypoxia might induce white matter damage during the perinatal period. Pregnant Sparague‐Dawley rats were placed in a chamber supplied with hypoxic gas (10% O2 ‐90% N2) from embryonic day 5(E5) to E20. Neonatal rat brains were investigated by histology, immunocytochemistry, western blotting, in situ hybridization, DNA fragmentation analysis, and in vivo magnetic resonance imaging (MRI).Body weight of pups subjected to prenatal hypoxia was 10 to 30% lower from p0 to P14 than in controls. Specific white matter cysts wear detected between p0 and p7 in pups subjected to prenatal hypoxia, in addition to abnormal extra‐cellular matrix, increased lipid peroxidation, white matter cell death detected by TUNEL and increased activated macrophage counts in white matter. Subsequently, gliotic scars and delayed myelination primarily involving immature oligodendrocytes were seen In vivo MRI with T1, T2, and diffusion sequences disclosed similar findings immediately after birth, showing strong correlations with histological abnormalities. We speculate that protracted prenatal hypoxia in rat induces abnormalities. We speculate that protracted prenatal hypoxia in rat induces white matter damage occurring through local inflammatory response and oxidative stress linked to re‐oxygenation during the perinatal period.
Methylene Blue Reduces Aβ Levels and Rescues Early Cognitive Deficit by Increasing Proteasome Activity
Authors: Medina David X. , Caccamo Antonella , Oddo Salvatore 
Published: July 2010

AbstractPromising results have emerged from a phase II clinical trial testing methylene blue (MB) as a potential therapeutic for Alzheimer disease (AD), where improvements in cognitive functions of AD patients after 6 months of MB administration have been reported. Despite these reports, no preclinical testing of MB in mammals has been published, and thus its mechanism of action in relation to AD pathology remains unknown. In order to elucidate the effects of MB on AD pathology and to determine its mechanism of action, we used a mouse model (3xTg‐AD) that develops age‐dependent accumulation of Aβ and tau and cognitive decline. Here, we report that chronic dietary MB treatment reduces Aβ levels and improves learning and memory deficits in the 3xTg‐AD mice. The mechanisms underlying the effects of MB on Aβ pathology appears to be mediated by an increase in Aβ clearance as we show that MB increases the chymotrypsin‐ and trypsin‐like activities of the proteasome in the brain. To our knowledge, this is the first report showing that MB increases proteasome function and ameliorates AD‐like pathology in vivo. Overall, the data presented here support the use of MB for the treatment of AD and offer a possible mechanism of action.
Alkane degradation under anoxic conditions by a nitrate‐reducing bacterium with possible involvement of the electron acceptor in substrate activation
Authors: Zedelius Johannes , Rabus Ralf , Grundmann Olav , Werner Insa , Brodkorb Danny , Schreiber Frank , Ehrenreich Petra , Behrends Astrid , Wilkes Heinz , Kube Michael , Reinhardt Richard , Widdel Friedrich 
Published: July 2010

SummaryMicroorganisms can degrade saturated hydrocarbons (alkanes) not only under oxic but also under anoxic conditions. Three denitrifying isolates (strains HxN1, OcN1, HdN1) able to grow under anoxic conditions by coupling alkane oxidation to CO2 with NO3‐ reduction to N2 were compared with respect to their alkane metabolism. Strains HxN1 and OcN1, which are both Betaproteobacteria, utilized n‐alkanes from C6 to C8 and C8 to C12 respectively. Both activate alkanes anaerobically in a fumarate‐dependent reaction yielding alkylsuccinates, as suggested by present and previous metabolite and gene analyses. However, strain HdN1 was unique in several respects. It belongs to the Gammaproteobacteria and was more versatile towards alkanes, utilizing the range from C6 to C30. Neither analysis of metabolites nor analysis of genes in the complete genome sequence of strain HdN1 hinted at fumarate‐dependent alkane activation. Moreover, whereas strains HxN1 and OcN1 grew with alkanes and NO3‐, NO2‐ or N2O added to the medium, strain HdN1 oxidized alkanes only with NO3‐ or NO2‐ but not with added N2O; but N2O was readily used for growth with long‐chain alcohols or fatty acids. Results suggest that NO2‐ or a subsequently formed nitrogen compound other than N2O is needed for alkane activation in strain HdN1. From an energetic point of view, nitrogen–oxygen species are generally rather strong oxidants. They may enable enzymatic mechanisms that are not possible under conditions of sulfate reduction or methanogenesis and thus allow a special mode of alkane activation.
Setup Time Reduction for Electronics Assembly: Combining Simple (SMED) and IT‐Based Methods
Authors: Trovinger Sheri Coble , Bohn Roger E. 
Published: July 2010

As much as 50% of effective capacity can be lost to setups in printed circuit board assembly. Shigeo Shingo showed that radical reductions in setup times are possible in metal fabrication using an approach he called “Single Minute Exchange of Dies” (SMED). We applied SMED to setups of high speed circuit board assembly tools. Its key concepts were valid in this very different industry, but while SMED typically emphasizes process simplification, we had to add modern information technology tools including wireless terminals, barcodes, and a relational database. These tools shield operators from the inherent complexity of managing thousands of unique parts and feeders. The economic value of setup reduction is rarely calculated. We estimate a reduction of key setup times by more than 80%, and direct benefits of $1.8 million per year. Total cost of the changes was approximately $350,000.
Costs of Bloodstream Infections Caused by
Escherichia coli
and Influence of Extended-Spectrum-β-Lactamase Production and Inadequate Initial Antibiotic Therapy
Authors: Tumbarello Mario , Spanu Teresa , Di Bidino Rossella , Marchetti Marco , Ruggeri Matteo , Trecarichi Enrico Maria , De Pascale Gennaro , Proli Enrica Maria , Cauda Roberto , Cicchetti Americo , Fadda Giovanni 
Published: July 2010

ABSTRACT

Escherichia coli
is the leading cause of bloodstream infections (BSIs) caused by Gram-negative bacteria. The increasing prevalence of antibiotic-resistant
E. coli
strains, particularly those producing extended-spectrum β-lactamases (ESBLs), increases the odds that empirically prescribed antimicrobial therapy for these infections will be inadequate, but the economic impact of this risk has not been fully evaluated. In the present retrospective 1-year analysis of 134 consecutive
E. coli
BSIs in our hospital, we explored the clinical and economic impacts of (i) inadequate initial antimicrobial treatment (IIAT) (i.e., empirical treatment with drugs to which the isolate had displayed
in vitro
resistance) of these infections and (ii) ESBL production by the bloodstream isolate. Cost data were obtained from the hospital accounting system. Compared with the 107 (79.8%) adequately treated patients, the 27 (20.1%) who received IIAT had a higher proportion of ESBL BSIs (74.0% versus 15.8%), longer (+6 days) and more costly (+EUR 4,322.00) post-BSI-onset hospital stays, and higher 21-day mortality rates (40.7% versus 5.6%). Compared with the 97 non-ESBL infections, the 37 (27.6%) ESBL BSIs were also associated with longer (+7 days) and more costly (+EUR 5,026.00) post-BSI-onset hospital stays and increased 21-day mortality (29.7% versus 6.1%). These findings confirm that the hospital costs and mortality associated with
E. coli
BSIs are significantly increased by ESBL production and by IIAT.
Lysyl-Phosphatidylglycerol Attenuates Membrane Perturbation Rather than Surface Association of the Cationic Antimicrobial Peptide 6W-RP-1 in a Model Membrane System: Implications for Daptomycin Resistance
Authors: Kilelee Erin , Pokorny Antje , Yeaman Michael R. , Bayer Arnold S. 
Published: July 2010

ABSTRACT
The presence of the cationic phospholipid lysyl-phosphatidylglycerol (lysyl-PG) in staphylococcal cytoplasmic membranes has been linked to increased resistance to cationic compounds, including antibiotics such as daptomycin as well as host defense antimicrobial peptides. We investigated the effects of lysyl-PG on binding of 6W-RP-1, a synthetic antimicrobial peptide, to lipid vesicles and on peptide-induced membrane permeabilization. Unexpectedly, physiological lysyl-PG concentrations only minimally reduced membrane binding of 6W-RP-1. In contrast, 6W-RP-1-induced dye leakage was severely inhibited by lysyl-PG, suggesting that lysyl-PG primarily impacts membrane defect formation.
Effects of Tuberculosis, Race, and Human Gene
SLCO1B1
Polymorphisms on Rifampin Concentrations
Authors: Weiner Marc , Peloquin Charles , Burman William , Luo Chi-Cheng , Engle Melissa , Prihoda Thomas J. , Mac Kenzie William R. , Bliven-Sizemore Erin , Johnson John L. , Vernon Andrew 
Published: July 2010

ABSTRACT

Rifampin has concentration-dependent activity against
Mycobacterium tuberculosis
. However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes
SLCO1B1
,
SLCO1B3
, and
MDR1
. Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC
0-24
] of 40.2 versus 40.9 μg·h/ml;
P
= 0.9). However, in multivariable analyses, the rifampin AUC
0-24
was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the
SLCO1B1
gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC
0-24
was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC
0-24
was also 36% lower among participants with
SLCO1B1
genotype c.463CA than that among participants with
SLCO1B1
genotype c.463CC (adjusted GM, 29.8 versus 46.7 μg·h/ml;
P
= 0.001). Polymorphisms in the
SLCO1B1
gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC
0-24
values was observed, but the mean values of the AUC
0-24
did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the
SLCO1B1
c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.
Discovery of Novel Orally Bioavailable Oxaborole 6-Carboxamides That Demonstrate Cure in a Murine Model of Late-Stage Central Nervous System African Trypanosomiasis
Authors: Nare Bakela , Wring Stephen , Bacchi Cyrus , Beaudet Beth , Bowling Tana , Brun Reto , Chen Daitao , Ding Charles , Freund Yvonne , Gaukel Eric , Hussain Ali , Jarnagin Kurt , Jenks Matthew , Kaiser Marcel , Mercer Luke , Mejia Elena , Noe Andy , Orr Matt , Parham Robin , Plattner Jacob , Randolph Ryan , Rattendi Donna , Rewerts Cindy , Sligar Jessica , Yarlett Nigel , Don Robert , Jacobs Robert 
Published: July 2010

ABSTRACTWe report the discovery of novel boron-containing molecules, exemplified byN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (AN3520) and 4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (SCYX-6759), as potent compounds againstTrypanosoma brucei in vitro, including the two subspecies responsible for human diseaseT. b. rhodesienseandT. b. gambiense.These oxaborole carboxamides cured stage 1 (hemolymphatic) trypanosomiasis infection in mice when administered orally at 2.5 to 10 mg/kg of body weight for 4 consecutive days. In stage 2 disease (central nervous system [CNS] involvement), mice infected withT. b. bruceiwere cured when AN3520 or SCYX-6759 were administered intraperitoneally or orally (50 mg/kg) twice daily for 7 days. Oxaborole-treated animals did not exhibit gross signs of compound-related acute or subchronic toxicity. Metabolism and pharmacokinetic studies in several species, including nonhuman primates, demonstrate that both SCYX-6759 and AN3520 are low-clearance compounds. Both compounds were well absorbed following oral dosing in multiple species and also demonstrated the ability to cross the blood-brain barrier with no evidence of interaction with the P-glycoprotein transporter. Overall, SCYX-6759 demonstrated superior pharmacokinetics, and this was reflected in better efficacy against stage 2 disease in the mouse model. On the whole, oxaboroles demonstrate potent activity against allT. bruceisubspecies, excellent physicochemical profiles,in vitrometabolic stability, a low potential for CYP450 inhibition, a lack of active efflux by the P-glycoprotein transporter, and high permeability. These properties strongly suggest that these novel chemical entities are suitable leads for the development of new and effective orally administered treatments for human African trypanosomiasis.
Rapid and Sensitive Liquid Chromatography/Mass Spectrometry Assay for Caspofungin in Human Aqueous Humor
Authors: Neoh Chin Fen , He Hui , Li Jian , Fullinfaw Robert O. , Leung Lok , Misra Anant , Vajpayee Rasik B. , Davies Geoffrey E. , Stewart Kay , Kong David C. M. 
Published: July 2010

ABSTRACT
A rapid, precise, and sensitive liquid chromatography/mass spectrometry (LC/MS) method to quantify the caspofungin concentration in human aqueous humor was developed and validated. Sample preparation involved simple dilution of aqueous humor samples with acetonitrile. Azithromycin was the internal standard. Good linearity over 10 to 5,000 ng/ml was observed. The lower limit of quantification was 10 ng/ml. The intra- and interday accuracies (percent bias) were within 11%, while the intra- and interday precisions were within 6%.
HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance
Authors: Rhee Soo-Yon , Taylor Jonathan , Fessel W. Jeffrey , Kaufman David , Towner William , Troia Paolo , Ruane Peter , Hellinger James , Shirvani Vivian , Zolopa Andrew , Shafer Robert W. 
Published: July 2010

ABSTRACTThe effects of many protease inhibitor (PI)-selected mutations on the susceptibility to individual PIs are unknown. We analyzedin vitrosusceptibility test results on 2,725 HIV-1 protease isolates. More than 2,400 isolates had been tested for susceptibility to fosamprenavir, indinavir, nelfinavir, and saquinavir; 2,130 isolates had been tested for susceptibility to lopinavir; 1,644 isolates had been tested for susceptibility to atazanavir; 1,265 isolates had been tested for susceptibility to tipranavir; and 642 isolates had been tested for susceptibility to darunavir. We applied least-angle regression (LARS) to the 200 most common mutations in the data set and identified a set of 46 mutations associated with decreased PI susceptibility of which 40 were not polymorphic in the eight most common HIV-1 group M subtypes. We then used least-squares regression to ascertain the relative contribution of each of these 46 mutations. The median number of mutations associated with decreased susceptibility to each PI was 28 (range, 19 to 32), and the median number of mutations associated with increased susceptibility to each PI was 2.5 (range, 1 to 8). Of the mutations with the greatest effect on PI susceptibility, I84AV was associated with decreased susceptibility to eight PIs; V32I, G48V, I54ALMSTV, V82F, and L90M were associated with decreased susceptibility to six to seven PIs; I47A, G48M, I50V, L76V, V82ST, and N88S were associated with decreased susceptibility to four to five PIs; and D30N, I50L, and V82AL were associated with decreased susceptibility to fewer than four PIs. This study underscores the greater impact of nonpolymorphic mutations compared with polymorphic mutations on decreased PI susceptibility and provides a comprehensive quantitative assessment of the effects of individual mutations on susceptibility to the eight clinically available PIs.
Colistin Dosing and Nephrotoxicity in a Large Community Teaching Hospital
Authors: DeRyke C. Andrew , Crawford Amanda J. , Uddin Nizam , Wallace Mark R. 
Published: July 2010

ABSTRACT

Thirty adult patients who received intravenous colistin (5.1 ± 2.4 mg/kg/day) were reviewed to evaluate dosing with respect to nephrotoxicity, which occurred in 10 (33%) patients within the first 5 days of treatment. Excessive colistin dosing was frequent (47%), often (71%) resulted from the use of actual body weight in obese patients, and was associated with higher rates of nephrotoxicity (80% versus 30%,
P
= 0.019).