The transmission of drug-resistant HIV in newly identified infected populations has become an underlying epidemic which can be better assessed with sensitive resistance testing. Since minority drug resistant variants cannot be detected by bulk sequencing, methods with improved sensitivity are required. Thus, the goal of this study was to evaluate if transmitted drug resistance mutations at minority levels in Japanese patients could be identified using highly sensitive allele-specific PCR (AS-PCR).
Materials and Methods
Samples were taken from newly diagnosed HIV/AIDS cases at the National Nagoya Hospital from January 2008 to December 2009. All samples were bulk sequenced for HIV protease and reverse transcriptase. To detect minority populations with drug resistance, we used AS-PCR with mutation-specific primers designed for seven reverse transcriptase inhibitor resistance mutations, M41L, K65R, K70R, K103N, Y181C, M184V, and T215F/Y, and for three protease inhibitor resistance mutations, M46I/L and L90M.
We studied 149 newly identified HIV cases. Bulk sequencing detected 8 cases with NRTI resistance mutations (one with A62V, one D67E, one T215D, one T215E, two with T215L and two T215S) and 15 with PI resistance mutations (one with N88D and 14 with M46I). Results obtained by AS-PCR and bulk sequencing demonstrated good concordance but the AS-PCR enabled the detection of seven additional drug-resistant cases (one M41L, two with K65R, two with K70R, and one M184V) in the RT region. Additionally, AS-PCR assays identified 15 additional cases with M46I, five with M46L and four cases with L90M in the protease region.
Using AS-PCR substantially increased the detection of transmitted drug resistance in this population from 15.4% to 26.8%, further supporting the benefit of sensitive testing among drug-naïve populations. Since the clinical impact of minority drug-resistant populations is not fully comprehended for all mutations, follow-up studies are needed to understand their significance for treatment.
The dynamic kinetic resolution of α-keto esters via asymmetric transfer hydrogenation has been developed as a technique for the highly stereoselective construction of structurally diverse β-substituted-α-hydroxy carboxylic acid derivatives. Through the development of a privileged m-terphenylsulfonamide for (arene)RuCl(monosulfonamide) complexes with a high affinity for selective α-keto ester reduction, excellent levels of chemo-, diastereo-, and enantiocontrol can be realized in the reduction of β-aryl- and β-chloro-α-keto esters.
Low socioeconomic status (SES) background has been identified as a risk for several mental disorders. However evidence regarding SES and the developmental course of personality disorder (PD) has not been addressed. Nor is it clear whether an SES relationship to PD symptom course may be attributable to known associated risks. Further, specificity of such relationships to a particular PD diagnostic pattern independent of comorbidity with other PD or with depression has not been investigated. Data are from a general population studied longitudinally between ages 10 and 36 in four assessment waves. Effects of SES-associated risks on the level of symptoms of schizotypal and borderline disorders are estimated and compared to effects on depressive symptoms. Low family SES had robust modest independent effects on both PDs over the entire age span despite substantial cumulative effects of trauma history, stressful recent life events, IQ, poor parenting, and comorbid symptoms. SES effects on depressive symptoms were generally absent, but a small “protective” effect of low SES appeared when comorbidity with PD symptoms was taken into account. Cumulatively, these risks account for developmental failures of substantial magnitude and consequence, marking the importance of understanding the remaining mechanisms of SES effects and programmatic implications for minimizing associated risk.
Aerobic hydroperoxidation of Meldrum’s acid derivatives via a Cu(II)-catalyzed process is presented. The mild reaction conditions are tolerant to pendant unsaturation allowing the formation of endoperoxides via electrophilic activation. Cleavage of the O–O bond provides 1,n-diols with differentiation of the hydroxy groups.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is the master transcription factor of the antioxidant response element (ARE) pathway, coordinating the induction of detoxifying and antioxidant enzymes. Nrf2 is normally sequestered in the cytoplasm by Kelch-like ECH associating protein 1 (Keap1). To identify novel small molecules that will disturb Nrf2:Keap1 binding and promote activation of the Nrf2-ARE pathway, we generated a quantum model based on the structures of known Nrf2-ARE activators. We used the quantum model to perform in silico screening on over 18 million commercially available chemicals to identify the structures predicted to activate the Nrf2-ARE pathway based on the quantum model. The top hits were tested in vitro and half of the predicted hits activated the Nrf2-ARE pathway significantly in primary cell culture. In addition, we identified a new family of Nrf2-ARE activating structures that all have comparable activity to tBHQ and protect against oxidative stress and dopaminergic toxins in vitro. The improved ability to identify potent activators of Nrf2 through the combination of in silico and in vitro screening described here improves the speed and cost associated with screening Nrf2-ARE activating compounds for drug development.
We recorded from middle-lateral (ML) and primary (A1) auditory cortex while macaques discriminated amplitude modulated (AM) from unmodulated noise. Compared to A1, ML had a higher proportion of neurons that encode increasing AM depth by decreasing their firing-rates (‘decreasing’ neurons), particularly with responses that were not synchronized to the modulation. Choice probability (CP) analysis revealed that A1 and ML activity were different during the first half of the test stimulus. In A1, significant CP begins prior to the test stimulus, remains relatively constant (or increases slightly) during the stimulus and increases greatly within 200 ms of lever-release. Neurons in ML behave similarly, except that significant CP disappears during the first half of the stimulus and reappears during the second half and pre-release periods. CP differences between A1 and ML depend on neural response type. In ML (but not A1), when activity is lower during the first half of the stimulus in non-synchronized ‘decreasing’ neurons, the monkey is more likely to report AM. Neurons that both increase firing rate with increasing modulation depth (‘increasing’ neurons) and synchronize their responses to AM had similar choice-related activity dynamics in ML and A1. The results suggest that, when ascending the auditory system, there is a transformation in coding AM from primarily synchronized ‘increasing’ responses in A1 to non-synchronized and dual (‘increasing’/’decreasing’) coding in ML. This sensory transformation is accompanied by changes in the timing of activity related to choice, suggesting functional differences between A1 and ML related to attention and/or behavior.
A study of the impacts on respiratory health of the 2007 wildland fires in and around San Diego County, California is presented. This study helps to address the impact of fire emissions on human health by modeling the exposure potential of proximate populations to atmospheric particulate matter (PM) from vegetation fires. Currently, there is no standard methodology to model and forecast the potential respiratory health effects of PM plumes from wildland fires, and in part this is due to a lack of methodology for rigorously relating the two. The contribution in this research specifically targets that absence by modeling explicitly the emission, transmission, and distribution of PM following a wildland fire in both space and time.
Coupled empirical and deterministic models describing particulate matter (PM) emissions and atmospheric dispersion were linked to spatially explicit syndromic surveillance health data records collected through the San Diego Aberration Detection and Incident Characterization (SDADIC) system using a Generalized Additive Modeling (GAM) statistical approach. Two levels of geographic aggregation were modeled, a county-wide regional level and division of the county into six sub regions. Selected health syndromes within SDADIC from 16 emergency departments within San Diego County relevant for respiratory health were identified for inclusion in the model.
The model captured the variability in emergency department visits due to several factors by including nine ancillary variables in addition to wildfire PM concentration. The model coefficients and nonlinear function plots indicate that at peak fire PM concentrations the odds of a person seeking emergency care is increased by approximately 50% compared to non-fire conditions (40% for the regional case, 70% for a geographically specific case). The sub-regional analyses show that demographic variables also influence respiratory health outcomes from smoke.
The model developed in this study allows a quantitative assessment and prediction of respiratory health outcomes as it relates to the location and timing of wildland fire emissions relevant for application to future wildfire scenarios. An important aspect of the resulting model is its generality thus allowing its ready use for geospatial assessments of respiratory health impacts under possible future wildfire conditions in the San Diego region. The coupled statistical and process-based modeling demonstrates an end-to-end methodology for generating reasonable estimates of wildland fire PM concentrations and health effects at resolutions compatible with syndromic surveillance data.
Wildland fire; Particulate matter emissions; Syndromic surveillance; Generalized additive modeling; Air quality; Respiratory health; San Diego County; California
The main objective of this review was to systematically review, assess, and report on the studies that have assessed health related quality of life (HRQOL) after VATS and thoracotomy for resection of lung cancer. We performed a systematic review of six databases. The Downs and Black tool was used to assess the risk of bias. Five studies were included. In general, patients undergoing VATS have a better HRQOL when compared to thoracotomy; however, there was a high risk of bias in the included studies. The consistent use of a lung cancer specific questionnaire for measuring HRQOL after surgery is encouraged.
Dual-process models of recognition memory distinguish between the retrieval of qualitative information about a prior event (recollection), and judgments of prior occurrence based on an acontextual sense of familiarity. fMRI studies investigating the neural correlates of memory encoding and retrieval conducted within the dual-process framework have frequently reported findings consistent with the view that the hippocampus selectively supports recollection, and has little or no role in familiarity-based recognition. An alternative interpretation of these findings has been proposed, however, in which it is argued that the hippocampus supports the encoding and retrieval of ‘strong’ memories, regardless of whether the memories are recollection- or familiarity-based. Here, we describe the findings of eight fMRI studies from our laboratory: one study of source memory encoding, four studies of the retrieval of contextual information, and three studies of continuous recognition. Together, the findings support the proposal that hippocampal activity co-varies with the amount of contextual information about a study episode that is encoded or retrieved, and not with the strength of an undifferentiated memory signal.
episodic memory; familiarity; memory strength; recollection; remember-know
We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced-intensity conditioning (RIC) regimen of fludarabine 150 mg/m2 plus intravenous busulfan 6.4 mg/kg. Both sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit anti-thymocyte globulin 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9 to 5.8), TRM at 6 months and 2 years was 8% and 23% respectively. Neither TRM nor the rates of acute GVHD were different in those with sibling or MUD donors. Donor CD3 cell chimerism > 90% at day +30 was achieved more often in patients with MUD than with MSD donors, 70% versus 23% (p<0.0001). Median EFS was higher in patients who achieved early full donor chimerism (14.2 versus 8 mo, p = 0.0395). Allo-HCT using this RIC regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve EFS.
Activation of the peroxisome proliferator activated receptor-gamma (PPAR)-γ is proposed as a neuroprotective strategy to treat neurodegenerative disorders. In this study, we examined if LSN862 (LSN), a novel non-thiazoledinedione partial PPAR-γ agonist, was neuroprotective in a mouse model of Parkinson's disease (PD) and assessed possible mechanisms of action. LSN (3, 10, or 30 mg/kg) or vehicle was orally administered daily to C57BL/6 and antioxidant response element-human placental alkaline phosphatase (ARE-hPAP) reporter mice 3 days prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg, i.p. × 5 days) or PBS administration. LSN elicited a dose-dependent preservation of dopaminergic nigrostriatal innervation that was not associated with inhibition of MPTP metabolism or activation of Nrf2-ARE, although changes in NQO1 and SOD2 mRNA were observed. A significant dose-dependent downregulation in MAC-1 and GFAP positive cells was observed in MPTP + LSN-treated mice as well as significant downregulation of mRNA expression levels of these inflammatory markers. MPTP-induced increases in PPAR-γ and PGC1α expression were ameliorated by LSN dosing. Our results demonstrate that oral administration of LSN is neuroprotective against MPTP-induced neurodegeneration, and this effect is associated with downregulation of neuroinflammation, decreased oxidative stress, and modulation of PPAR-γ and PGC1α expression. These results suggest that LSN can be a candidate alternative non-thiazoledinedione partial PPAR-γ agonist for neuroprotective treatment of PD.
Thirty years ago we reported our experience with abdominal vascular trauma, highlighting the critical role of hypothermia, acidosis, and coagulopathy. Damage control surgery was subsequently introduced to address this “lethal triad.” The purpose of this study is to evaluate outcomes from our most recent 6-year experience compared to 30 years ago.
Patients with major abdominal vascular injuries were examined; the most recent 6-year period was compared with archived data from a similar 6-year period three decades ago.
The number of patients with major abdominal vascular injuries decreased from 123 patients (1975–1980) to 64 patients (2004–2009). The mean initial pH decreased from 7.21 to 6.96 (1975–1980 vs. 2004–2009]) for patients with overt coagulopathy. In spite of increasingly protracted acidosis, mortality attributable to refractory coagulopathy has decreased from 46% to 19% (1975–1980 vs. 2004–2009, χ2 = 4.36, p = 0.04). There was no significant difference in mortality due to exsanguinating injuries (43% vs. 62%, 1975–1980 vs. 2004–2009, χ2 = 1.96, p = 0.16). Prehospital transport times were unchanged (22 min vs. 20 min, 1975–1980 vs. 2004–2009). Despite the administration of additional clotting factors and the advent of DCS, the overall mortality remains largely unchanged (37% vs. 33%, 1975–1980 vs. 2004–2009, χ2 = 0.385, p = 0.53).
Adoption of damage control surgery, including the implementation of a massive transfusion protocol, is associated with a reduction in mortality for abdominal vascular injuries due to coagulopathy, however, patients continue to die from exsanguination.
damage control surgery; abdominal vascular trauma; massive transfusion; coagulopathy; blunt trauma; penetrating trauma; exsanguination
The current generation of blood substitutes tested in clinical trials are red blood cell (RBC) substitutes; that is, they are designed primarily to transport oxygen. The products now being used in advanced-phase clinical trials are derived from hemoglobin (Hb) and are thus often referred to as Hb-based oxygen carriers (HBOCs). The potential benefits of HBOCs are well known (Box 1). The objectives of this overview are to provide the scientific background and rationale for the study design of the USA Multi-center Prehospital HBOC Resuscitation Trial and to present the results and discuss clinical implications.
Box 1Potential clinical benefits of hemoglobin-based oxygen carriers in trauma careAvailabilityAbundant supplyUniversally compatibleProlonged shelf-lifeStorage at room temperatureSafetyNo disease transmissionsNo antigenic reactionsNo immunologic effectsEfficacyEnhanced oxygen deliveryImproved rheologic properties
Hemoglobin-based oxygen carrier; Blood substitute Prehospital resuscitation; Hemorrhagic shock; Trauma
fMRI responses to recognition memory test items in two regions of ventral lateral parietal cortex—the angular gyrus and temporo-parietal junction (TPJ)—are enhanced when recognition is accompanied by recollection. According to the ‘episodic buffer’ hypothesis, ventral parietal recollection effects reflect processes involved in maintaining or representing recollected information. According to the ‘attention to memory’ hypothesis, however, the effects reflect attentional re-orienting to the products of recollection. The present experiment addressed the question whether these operations map on to the angular gyrus and TPJ, respectively. Subjects were scanned during a memory test that required a Remember/Know/New and a source memory judgment, allowing recollected items to be segregated by amount of contextual information recollected. Angular gyrus activity tracked amount of recollected information, whereas activity in the TPJ was enhanced for items endorsed as recollected, but was insensitive to amount of information recollected. Thus, the two regions likely support functionally dissociable processes.
Human episodic memory; fMRI; Lateral parietal cortex; Source memory; Recollection; Confidence
While minimizing hyperglycemia in critically injured patients improves outcomes, it is debatable whether postinjury glucose control should aim for conventional (CGC≤180mg/dL) or tight levels (TGC=81–108mg/dL). Thus, we queried our 17-year prospective database of patients at risk for postinjury multiple organ failure to examine the association between glucose levels and adverse outcomes.
Acutely injured patients admitted to a Level I trauma center intensive care unit from 1992 to 2008 with age>15, injury severity score (ISS)>15, and survival>48hrs were eligible for the study. Multiple logistic regression was used to determine the independent association of glucose control with adverse outcomes (death, ventilator free days, ICU free days, and major infections), adjusted for ISS, age, and red blood cell transfusion in the first 12 hours (RBC/12hrs).
Overall, 2231 patients were eligible, of whom 153 (6.9%) died. Mean age was 37.8±0.4 years and median ISS was 27 (IQR:21–35). The majority (77%) of these patients maintained mean glucose within CGC and only 10% achieved mean glucose levels within TGC. Non-survivors required higher doses of insulin to control glucose levels, showing higher mean insulin:glucose ratios (t-test, p=0.025). After adjusting for confounders, mean glucose remained significantly associated with the studied adverse outcomes. Age significantly modified all these associations, with older patients, seeming to benefit more from TGC than their younger counterparts.
Age is an effect modifier of the association between glucose levels and adverse outcomes. Future studies including larger samples of elderly trauma patients are needed to determine the ideal levels for glucose control in this growing population.
hyperglycemia; critical care; geriatric; elderly; glucose control
Novel bone turnover markers could help with the diagnosis and monitoring of osteomyelitis patients. We compared levels of two bone turnover markers, serum amino-terminal telopeptides (NTx) and bone alkaline phosphatase (BAP), in diabetic patients with and without osteomyelitis.
Matched case-control study was conducted with diabetic patients with and without osteomyelitis. Cases not undergoing immediate amputation were followed with repeat measurements after osteomyelitis treatment and for outcome determination.
Analysis included 54 subjects, 27 cases and 27 controls. Median BAP levels were similar between cases and controls at enrollment (p=.55) as were median NTx levels (p=.43). Cases with follow-up data (n = 18) had similar bone marker levels at enrollment and 6 weeks. No significant differences in BAP or NTx levels at enrollment or follow-up were seen between cases with poor versus favorable outcomes.
No differences in NTx or BAP levels were seen between cases and controls. Cases with follow-up data had similar levels at enrollment and 6 weeks. Lack of difference may be due to small sample size, small areas of bone involved in foot osteomyelitis, or limitations of these specific markers. More research is needed.
Osteomyelitis; diabetic foot ulcers; bone markers; treatment outcomes
High forefoot plantar pressure is associated with plantar ulcers in people with diabetes and peripheral neuropathy. The purpose of this pilot study is to determine safety and efficacy of botulinum toxin A injected into the gastrocnemius-soleus muscles to reduce muscle strength and plantar pressure.
Materials and Methods
This double blind, randomized clinical trial studied 17 people with diabetes mellitus, peripheral neuropathy and forefoot plantar ulcer. Subjects were randomized into one of three groups receiving gastrocnemius-soleus muscle injections on the involved side with; 1) Saline (n=5, weight = 99 ± 21 kg), 2) 200 units of Botox® (n=7, weight = 101 ± 5 kg), or 3) 300 units of Botox® (n=5, weight=129 ± 22 kg). Botox® dose was converted to units/kg, the majority received between 1.9 and 2.4 units/kg (n=11) and one 3.2 units/kg. Plantarflexor peak torque and forefoot peak plantar pressure were quantified prior and two weeks post injection.
There were no complications from the injections. Plantarflexor peak torque on the involved side increased in the placebo and 300 groups (3 ± 4 Nm and 6 ± 10 Nm respectively) and decreased −8 ± 11 Nm in the 200 group. There was no relationship between units/kg of Botox® for each subject and change in plantarflexor peak torque. Forefoot peak plantar pressure did not change in the placebo and 300 groups (0 ± 11 and 0 ± 5 N/cm2 respectively) and decreased −4 ± 16 N/cm2 (4%) for the 200 group.
There were no adverse events associated with the Botox® injections. This study was unable to determine the dose to consistently reduce plantarflexor strength and forefoot plantar pressure. Additional research is needed to investigate diabetes mellitus specific physiological changes and their impact of BoNT-A effectiveness in order to guide appropriate dosing.
Botulinum Toxin A; peripheral nervous system diseases; diabetes mellitus
α-Aminations of ketone-derived nitrones have been developed via [3,3]-rearrangement of the intermediates generated upon condensation with imidoyl chlorides. Careful reagent selection provides synthetically attractive amino protecting groups. The enediamide or α′-carbamoyl enamide products can be hydrolyzed to the desired carbonyl, or exposed to electrophiles for further α-functionalization.
The Nrf2 (NF-E2 related factor 2)-ARE (antioxidant response element) pathway controls a powerful array of endogenous cellular antioxidant systems and is an important pathway in the detoxification of reactive oxygen species (ROS) in the brain. Using a combination of quantitative proteomics and siRNA screening, we have identified novel protective mechanisms of the Nrf2-ARE pathway against oxidative stress in astrocytes. Studies from our lab and others have shown Nrf2 overexpression protects astrocytes from oxidative stress. However, the exact mechanisms by which Nrf2 elicits these effects are unknown. In this study, we show that induction of Nrf2 reduces levels of reactive oxygen species (ROS) produced by various oxidative stressors and results in robust cytoprotection. To identify the enzymes responsible for these effects, we used stable isotope labeling by amino acids in cell culture (SILAC) and quantitative shotgun proteomics to identify 72 Nrf2-regulated proteins in astrocytes. We hypothesized a subset of these proteins might play a critical role in Nrf2 protection. In order to identify these critical proteins, we used bioinformatics to narrow our target list of proteins and then systematically screened each candidate with siRNA to assess the role of each in Nrf2 protection. We screened each target against H2O2, tert-butyl hydroperoxide, and 4-hydroxynonenal and subsequently identified three enzymes–catalase, prostaglandin reductase-1, and peroxiredoxin-6–that are critical for Nrf2-mediated protection in astrocytes.
Genetic interactions reveal the functional relationships between pairs of genes. In this study, we describe a method for the systematic generation and quantitation of triple mutants, termed Triple Mutant Analysis (TMA). We have used this approach to interrogate partially redundant pairs of genes in S. cerevisiae, including ASF1 and CAC1, two histone chaperones. After subjecting asf1Δ cac1Δ to TMA, we found that the Swi/Snf Rdh54 protein, compensates for the absence of Asf1 and Cac1. Rdh54 more strongly associates with the chromatin apparatus and the pericentromeric region in the double mutant. Moreover, Asf1 is responsible for the synthetic lethality observed in cac1Δ strains lacking the HIRA-like proteins. A similar TMA was carried out after deleting both CLB5 and CLB6, cyclins that regulate DNA replication, revealing a strong functional connection to chromosome segregation. This approach can reveal functional redundancies that cannot be uncovered using traditional double mutant analyses.
Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.
Resistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.
Four weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).
Detection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.
Catalytic direct aldol addition of α-hydroxy trialkyl phosphonacetates to aldehydes affords α-hydroxy-β-phosphonyloxy ester products. The fully substituted glycolate enolate intermediate is generated in situ under mild conditions via [1,2]-phosphonate-phosphate rearrangement. High enantioselectivity and dramatic enhancement of reaction diastereocontrol is realized via the application of chiral iminophosphorane catalysts. The phosphate products undergo stereoselective nucleophilic displacement reactions.
Direct Aldol Reaction; Phosphate; Rearrangement; Enantioselective
Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD 19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively (p = 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively (p = 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma.
Lymphoma; anti-B4-blocked ricin; autologous transplant; adjuvant therapy
Alpha synuclein (SYN) is a central player in the pathogenesis of sporadic and familial Parkinson’s disease (PD). SYN aggregation and oxidative stress are associated and enhance each other’s toxicity. It is unknown whether the redox sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a role against the toxicity of SYN. To examine this, mice selectively overexpressing Nrf2 in astrocytes (GFAP-Nrf2) were crossed with mice selectively expressing human mutant SYN (hSYNA53T) in neurons. Increased astrocytic Nrf2 delayed the onset and extended the life span of the hSYNA53T mice. This correlated with increased motor neuron survival, reduced oxidative stress, and attenuated gliosis in the spinal cord, as well as a dramatic decrease in total hSYNA53T and phosphorylated (Ser129) hSYNA53T in triton-insoluble aggregates. Furthermore, Nrf2 in astrocytes delayed chaperone-mediated autophagy (CMA) and macroautophagy dysfunction observed in the hSYNA53T mice. Our data suggest that Nrf2 in astrocytes provides neuroprotection against hSYNA53T-mediated toxicity by promoting the degradation of hSYNA53T through the autophagy-lysosome pathway (ALP) in vivo. Thus, activation of the Nrf2 pathway in astrocytes is a potential target to develop therapeutic strategies for treating pathologic synucleinopathies including PD.
It has been proposed that the hippocampus selectively supports retrieval of contextual associations, but an alternative view holds that the hippocampus supports strong memories regardless of whether they contain contextual information. We employed a memory test that combined the ‘Remember/Know’ and source memory procedures, and that allowed test items to be segregated both by memory strength (recognition accuracy) and, separately, by the quality of the contextual information that could be retrieved (indexed by the accuracy/confidence of a source memory judgment). As measured by fMRI, retrieval-related hippocampal activity tracked the quality of retrieved contextual information and not memory strength. These findings are consistent with the proposal that the hippocampus supports contextual recollection rather than recognition memory more generally.
recollection; familiarity; retrieval; fMRI