Transient heating in fixed length optical cavities for use as temperature and pressure standards.

Optical refractometry techniques enable realization of both pressure and temperature directly from properties of the gas. The NIST refractometer, a fixed length optical cavity (FLOC) has previously been evaluated for operation as pressure standard, and now in this paper, is evaluated for the feasibility of operation as a primary temperature standard as well. The challenge is that during operation, one cavity is filled with gas. Gas dynamics predicts that this will result in heating which in turn will affect the cavity temperature uniformity, impeding the ability to measure the gas temperature with sufficient accuracy to make the standard useful as a primary standard for temperature or pressure. Temperature uniformity across the refractometer must be less than 0.5 mK for measurements of the refractivity to be sufficiently accurate for the FLOC. This paper compares computer modeling to laboratory measurements, enabling us to validate the model to predict thermal behavior and to accurately determine the measurement uncertainty of the technique. The results presented in this paper show that temperature of the glass elements of the refractometer and 'thermal-shell' copper chamber are equivalent to within 0.5 mK after an equilibration time of 3000 s (when going from 1 kPa to 100 kPa). This finding enables measurements of the copper chamber to determine the gas temperature to within an uncertainty (k = 1) of 0.5 mK. Additionally, the NIST refractometer is evaluated for feasibility of operation as temperature standard.

Isomerization of trans-3-methylglutaconic acid.

3-Methylglutaconic (3MGC) aciduria is a common phenotypic feature of a growing number of inborn errors of metabolism. "Primary" 3MGC aciduria is caused by deficiencies in leucine pathway enzymes while "secondary" 3MGC aciduria results from inborn errors of metabolism that impact mitochondrial energy production. The metabolic precursor of 3MGC acid is trans-3MGC CoA, an intermediate in the leucine catabolism pathway. Gas chromatography-mass spectrometry (GC-MS) analysis of commercially available trans-3MGC acid yielded a mixture of cis and trans isomers while 1H-NMR spectroscopy of trans-3MGC acid at 25°C provided no evidence for the cis isomer. When trans-3MGC acid was incubated under conditions used for sample derivatization prior to GC-MS (but with no trimethylsilane added), 1H-NMR spectroscopy provided evidence of trans to cis isomerization. Incubation of trans-3MGC acid at 37°C resulted in time-dependent isomerization to cis-3MGC acid. Cis-3MGC acid behaved in a similar manner except that, under identical incubation conditions, less isomerization occurred. In agreement with these experimental results, molecular modeling studies provided evidence that the energy minimized structure of cis-3MGC acid is 4 kJ/mol more stable than that for trans-3MGC acid. Once generated in vivo, trans-3MGC acid is proposed to isomerize via a mechanism involving π electron delocalization with formation of a resonance structure that permits bond rotation. The data presented are consistent with the occurrence of both diastereomers in urine samples of subjects with 3MGC aciduria.

Quantum-Based Photonic Sensors for Pressure, Vacuum, and Temperature Measurements: A Vison of the Future with NIST on a Chip.

The NIST on a Chip (NOAC) program's central idea is the idea that measurement technology can be developed to enable metrology to be performed "outside the National Metrology Institute" by the creation of deployed and often miniaturized standards. These standards, when based on fundamental properties of nature, are directly tracible to the international system of units known as the SI. NIST is also developing quantum-based standards for SI traceability known as QSI, or Quantum based International System of units. Specifically, this paper will cover NIST efforts in the area of thermodynamic metrology to develop NOAC standards for pressure, vacuum and temperature measurements.

Nitrous Oxide-Promoted Pauson-Khand Cycloadditions.

A Pauson-Khand cycladdition of alkynes, alkenes, and carbon monoxide, promoted by cobalt carbonyl and nitrous oxide to furnish cyclopentenones is described. Preliminary mechanistic experiments suggest that nitrous oxide functions in a similar manner to the N-oxide promoters typically employed in Pauson-Khand reactions. Only dinitrogen and carbon dioxide are produced as a consequence of the activation mechanism, thus avoiding high molecular weight reagents and the build up of basic byproducts. The chemistry is done using equimolar amounts of alkyne, alkene, and dicobalt octacarbonyl, and is performed directly from the acetylenic component without having to presynthesize a cobalt-alkyne complex. Terminal acetylenes were suitable substrates, as was solid calcium carbide, and the corresponding adducts were isolated in good yields. Furthermore, two sequential [4+3] and [2+2+1] cycloadditions were performed, generating funtionalized cyclopentenones in only two steps from readily available starting materials.

Towards Photonic based Pascal Realization as a Primary Pressure Standard.

New techniques using refractometry have enabled gas pressure to be measured using laser interferometry. Two key techniques have been studied at NIST which include the Fixed Length Optical Cavity (FLOC) and the Variable Length Optical Cavity (VLOC). The measurement techniques are described and the traceability of these measurements through quantum mechanics that enables them to be primary standards. This technology is critical for gas pressure metrology to move away from artifact based standards (and especially mercury based) and move to quantum based methods for realization of the pascal.

Recent Advances in the Pauson-Khand Reaction.

The Pauson-Khand [2+2+1] cycloaddition of alkynes, alkenes, and carbon monoxide has been a vibrant area of research for more than 40 years. This review highlights recent achievements in the Pauson-Khand reaction, particularly in catalytic and asymmetric variants. Discussion of regioselectivity and advances in substrate scope is also presented.

Biophysics of zebrafish (Danio rerio) sperm.

In the past two decades, laboratories around the world have produced thousands of mutant, transgenic, and wild-type zebrafish lines for biomedical research. Although slow-freezing cryopreservation of zebrafish sperm has been available for 30 years, current protocols lack standardization and yield inconsistent post-thaw fertilization rates. Cell cryopreservation cannot be improved without basic physiological knowledge, which was lacking for zebrafish sperm. The first goal was to define basic cryobiological values for wild-type zebrafish sperm and to evaluate how modern physiological methods could aid in developing improved cryopreservation protocols. Coulter counting methods measured an osmotically inactive water fraction (Vb) of 0.37+/-0.02 (SEM), an isosmotic cell volume (V(o)) of 12.1+/-0.2 microm(3) (SEM), a water permeability (L(p)) in 10% dimethyl sulfoxide of 0.021+/-0.001(SEM)microm/min/atm, and a cryoprotectant permeability (P(s)) of 0.10+/-0.01 (SEM)x10(-3)cm/min. Fourier transform infrared spectroscopy indicated that sperm membranes frozen without cryoprotectant showed damage and lipid reorganization, while those exposed to 10% glycerol demonstrated decreased lipid phase transition temperatures, which would stabilize the cells during cooling. The second goal was to determine the practicality and viability of shipping cooled zebrafish sperm overnight through the mail. Flow cytometry demonstrated that chilled fresh sperm can be maintained at 92% viability for 24h at 0 degrees C, suggesting that it can be shipped and exchanged between laboratories. Additional methods will be necessary to analyze and improve cryopreservation techniques and post-thaw fertility of zebrafish sperm. The present study is a first step to explore such techniques.

Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma.

BACKGROUND: Vorinostat has demonstrated activity in refractory cutaneous T-cell lymphoma. In a phase I trial, an encouraging activity in diffuse large-B-cell lymphoma (DLBCL) was noted. PATIENTS AND METHODS: We carried out a phase II trial (NCT00097929) of oral vorinostat 300 mg b.i.d. (14 days/3 weeks or 3 days/week) in patients with measurable, relapsed DLBCL who had received two or more systemic therapies. Response rate and duration (DOR), time to progression (TTP) and safety were assessed. RESULTS: Eighteen patients were enrolled (median age: 66 years; median prior therapies: 2). Seven received 300 mg b.i.d. 14 days/3 weeks, but four had grade 3 or 4 toxicity (dose-limiting toxicity, DLT). The schedule was amended to 300 mg b.i.d. 3 days/week), and none had DLT. One achieved a complete response (TtR = 85 days; DOR =or >468 days) and one had stable disease (301 days). Sixteen discontinued for progressive disease; median TTP was 44 days. Median number of cycles was 2 (1 to >19). Common drug-related adverse experiences (AEs; mostly grade 1/2) were diarrhea, fatigue, nausea, anemia and vomiting. Three patients had dose reduction; none discontinued for drug-related AEs. Drug-related AE >or=grade 3 included thrombocytopenia (16.7%) and asthenia (11.1%). CONCLUSION: Vorinostat was well tolerated at 300 mg b.i.d. 3 days/week or 200 mg b.i.d. 14 days/3 weeks but had limited activity against relapsed DLBCL.

Equine sperm membrane phase behavior: the effects of lipid-based cryoprotectants.

The plasma membrane of sperm can undergo lipid phase separation during freezing, resulting in irreversible damage to the cell. The objective of our study was to examine the membrane phase behavior of equine spermatozoa in the absence and presence of lipid-based cryoprotectants. Biophysical properties of sperm membranes were investigated with Fourier-transform infrared spectroscopy. Compared to fresh untreated sperm, postthaw untreated sperm showed extensive lipid phase separation and rearrangement. In contrast, postthaw sperm that were cryopreserved in egg phosphatidylcholine (egg PC)- or soy phosphatidylcholine (soy PC)-based diluents showed similar lipid phase behavior to that of fresh, untreated sperm. Studies with a deuterium-labeled PC lipid (POPCd-31) suggest that exogenous lipid from the diluents are strongly associated with the sperm membrane, and scanning electron microscopy images of treated sperm show the presence of lipid aggregates on the membrane surface. Thus, the exogenous lipid does not appear to be integrated into the sperm membrane after cryopreservation. When compared to a standard egg-yolk-based diluent (INRA 82), the soy and egg PC media preserved viability and motility equally well in postthaw sperm. A preliminary fertility study determined that sperm cryopreserved in the soy PC-based medium were capable of fertilization at the same rate as sperm frozen in the conventional INRA 82 medium. Our results show that pure lipid-based diluents can prevent membrane damage during cryopreservation and perform as well as a standard egg-yolk-based diluent in preserving sperm viability, motility, and fertility.

An investigation of working memory rehearsal in multiple sclerosis using fMRI.

The present study examined patterns of cerebral activation during a working memory (WM) rehearsal task in individuals diagnosed with multiple sclerosis (MS) and in healthy adults. BOLD functional magnetic resonance imaging (fMRI) was performed using a 1.5 T GE scanner to assess activation during a WM task adapted from the Sternberg paradigm (Sternberg, 1969). Participants included 8 individuals diagnosed with MS, and 5 healthy controls (HCs) matched for age and education. Task difficulty was manipulated by increasing the length of time that strings of letters were to be rehearsed. Findings revealed increased right prefrontal cortex activation and increased right temporal lobe activation in individuals diagnosed with MS compared to HCs. The potential explanations for increased right hemisphere activation in persons with MS are discussed.

Functional magnetic resonance imaging of working memory impairment after traumatic brain injury.

OBJECTIVES: To examine patterns of brain activation while performing a working memory task in persons with moderate to severe traumatic brain injury (TBI) and healthy controls. It is well established that working memory is an area of cognition that is especially vulnerable to disruption after TBI. Although much has been learned about the system of cerebral representation of working memory in healthy people, little is known about how this system is disrupted by TBI. METHODS: Functional magnetic resonance imaging (fMRI) was used to assess brain activation during a working memory task (a modified version of the paced auditory serial addition test) in nine patients with TBI and seven healthy controls. RESULTS: Patients with TBI were able to perform the task, but made significantly more errors than healthy controls. Cerebral activation in both groups was found in similar regions of the frontal, parietal, and temporal lobes, and resembled patterns of activation found in previous neuroimaging studies of working memory in healthy persons. However, compared with the healthy controls, the TBI group displayed a pattern of cerebral activation that was more regionally dispersed and more lateralised to the right hemisphere. Differences in lateralisation were particularly evident in the frontal lobes. CONCLUSIONS: Impairment of working memory in TBI seems to be associated with alterations in functional cerebral activity.

Long-term neuropsychological outcome after traumatic brain injury.

OBJECTIVE: To describe neuropsychological outcome 5 years after injury in persons with traumatic brain injury (TBI) who received inpatient medical rehabilitation. To determine the magnitude and pattern neuropsychological recovery from 1 year to 5 years after injury. DESIGN: Longitudinal cohort study with inclusion based on the availability of neuropsychological data at 1 year and 5 years after injury. SETTING: National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems of Care. PARTICIPANTS: One hundred eighty-two persons with complicated mild to severe traumatic brain injury. PRIMARY OUTCOME MEASURES: Digits Forward and Backward, Logical Memory I and II, Token Test, Controlled Oral Word Association Test, Symbol Digit Modalities Test, Trail Making Test, Rey Auditory Verbal Learning Test, Visual Form Discrimination, Block Design, Wisconsin Card Sorting Test, and Grooved Pegboard. RESULTS: Significant variability in outcome was found 5 years after TBI, ranging from no measurable impairment to severe impairment on neuropsychological tests. Improvement from 1 year after injury to 5 years was also variable. Using the Reliable Change Index, 22.2% improved, 15.2% declined, and 62.6% were unchanged on test measures. CONCLUSIONS: Neuropsychological recovery after TBI is not uniform across individuals and neuropsychological domains. For a subset of persons with moderate to severe TBI, neuropsychological recovery may continue several years after injury with substantial recovery. For other persons, measurable impairment remains 5 years after injury. Improvement was most apparent on measures of cognitive speed, visuoconstruction, and verbal memory.

Verbal recall and recognition following traumatic brain injury: a [0-15]-water positron emission tomography study.

Although several studies exist which have examined static functional neuroimaging following traumatic brain injury (TBI), controlled cognitive activation studies of episodic memory in this population have not been published. The present investigation studied verbal recall using [O-15]-water positron emission tomography (PET) in 5 individuals who sustained severe TBI (M GCS=6.8; M years post-injury=3.18), and 4 non-injured control participants. Statistical image analysis demonstrated changes in frontoparietal regional cerebral blood flow (rCBF) in both groups, but there were interesting differences between groups and across conditions. Frontal lobe rCBF changes in TBI patients were reduced during free recall but enhanced during recognition, when compared to controls. Changes in cerebellar rCBF were observed in the control group during free recall, but not in the TBI sample. In both groups, bifrontal rCBF increases were noted on recognition tasks. The present findings provide evidence of alterations in specific substrates involved in verbal recall following brain injury.

Functionally activated brain imaging (O-15 PET and fMRI) in the study of learning and memory after traumatic brain injury.

Advances in functional imaging technology and cognitive neuropsychology have resulted in paradigms in which participants can perform cognitive tasks during functional image acquisition. We will discuss the application of two approaches (oxygen-15 positron emission tomography and functional magnetic resonance imaging) that have recently been used to examine components of learning and memory following traumatic brain injury (TBI). Activated functional brain imaging findings that we will discuss may suggest possible functional reallocation and reorganization of brain substrates involved in verbal learning and memory following brain injury. The findings also are clearly in line with other research that indicates a prominent role for the frontal lobes in learning and memory functioning, and support the concept of distributed neural networks for memory-related functions, cognitive load, and the potential for examining brain re-organization after injury.

Fractioning the Hooper: a multiple-choice response format.

The Hooper Visual Organization Test (HVOT) provides an excellent illustration of the multifactorial nature of most neuropsychological tests. Although the HVOT clearly requires certain visual perceptual skills, the test also demands that the subject produce an overt verbal response - i.e., the name of the object that has been cut up and rearranged. Thus, individuals with disorders of confrontation naming may obtain low scores on the HVOT by virtue of their anomia, even if the primary perceptual skills that the HVOT purports to assess are intact. The present study was designed to minimize the demands of object naming on HVOT performance, by using a multiple choice format of the HVOT. Fourteen individuals with lateralized injury resulting from either cerebral vascular accident or cerebral contusion were administered the Boston Naming Test (BNT) and the standard version of the HVOT. Approximately 24 hours later, subjects were administered the Multiple-Choice Hooper Visual Organization Test (MC-HVOT). The MC-HVOT consisted of the 30 original HVOT stimuli presented with four response choices, including the correct response and three foils. A paired sample t test revealed that anomic subjects achieved a significantly greater number of correct responses on the MC-HVOT then under the standard HVOT administration. Subjects with both right and left hemisphere involvement benefited from diminished naming demands. Overall HVOT performance significantly improved when the object naming demand was reduced, resulting in a clearer assessment of visual integration skills. These findings may have significant implications for both interpretation of impairment and formulation of treatment recommendations.

The hippocampus: anatomy, pathophysiology, and regenerative capacity.

Cognitive deficits following insults to the central nervous system-particularly those involving the hippocampus and related structures-are often persistent and severely debilitating. Progress has been made in establishing the role of the hippocampus in integrating information in the formation of memory necessary for subsequent recollection of information. The present article will review anatomic, physiological, and functional aspects of the hippocampus in reference to learning and memory. Both animal and human hippocampal pathophysiological processes will be explored. Adaptive and maladaptive central nervous system responses will be reviewed, with a special emphasis on neurogenesis. Ideally, physiological and cellular compensatory responses ought to parallel clinical observation. However, this association is not clearly established. Finally, the current understanding of neuromodulatory mechanisms (although quite preliminary) will also be discussed.

Functional neuroimaging and quantitative electroencephalography in adult traumatic head injury: clinical applications and interpretive cautions.

Functional neuroimaging and quantitative electroencephalographic procedures are being used increasingly in brain injury research and clinical care. These procedures are also seeing increased use in the context of forensic evaluations, particularly in cases of mild head trauma. This article provides an overview of the use of procedures such as positron emission tomography, single photon emission computed tomography, and quantitative electroencephalogram in adults. Also discussed are the clinical limitations of each procedure within the context of myriad interpretive confounds that can interfere with accurate differential diagnosis of mild head trauma.

Learning impairment is associated with recall ability in multiple sclerosis.

Recent evidence suggests that persons with multiple sclerosis may experience deficits in verbal and visuospatial acquisition rather than recall. The present study was designed to determine whether this finding generalized to a broader range of neuropsychological tests of learning and memory. To control for group differences in information acquisition, healthy controls (HCs) and persons with multiple sclerosis (MS) were trained to specific learning criteria on both verbal (i.e., paragraph learning and paired associates) and visuospatial (i.e., facial recognition) memory tasks. Persons with MS required significantly more learning trials to meet criteria on the paragraph learning and facial recognition tasks, but not the paired associates test. However, after learning comparable amounts of information, the MS and HC groups recalled statistically similar amounts of information at 30-minutes, 90-minutes, and up to 1-week on the paragraph learning and paired associate tests. This suggests that persons with MS may have deficits in acquisition rather than recall per se. Results are discussed in terms of possible rehabilitation strategies to improve memory functioning in persons with MS.

Diagnostic efficiency and material specificity of the Warrington Recognition Memory Test: a collaborative multisite investigation.

Two studies examined the Warrington Recognition Memory Test (RMT) discrepancy index (Words-Faces) in a large sample of patients heterogeneous with respect to age, education, gender, and neurological diagnosis. In Study 1 (N = 504) we used cutoffs from the Words-Faces discrepancy scores derived from Warrington's original validation sample to attempt to accurately classify patients with left, right, or diffuse brain damage. Sensitivity for left hemisphere patients (Faces > Words) was 10% with a specificity of 88%, whereas sensitivity for right hemisphere patients (Words > Faces) was 48% with a specificity of 86%. For patients with diffuse brain damage (Words = Faces) sensitivity was 69% and specificity was 38%. In Study 2 (N = 263), we examined the relationship between the Words-Faces discrepancy score and Wechsler Memory Scale-Revised (WMS-R; Wechsler, 1981) Logical Memory and Visual Reproduction subtests. Contrary to predictions, patients with Words > Faces performed better on both WMS-R subtests; the Faces > Words discrepancy was not related to Visual Reproduction performance. Potential reasons for these negative findings are discussed, as well as cautions for future RMT discrepancy index use.

Use of biomarkers in an indoor air study: lack of correlation between aromatic VOCs with respective urinary biomarkers.

The benzene and toluene levels inside of eight homes with attached garages were measured during July 1998 in Fairbanks, Alaska. A thermal desorption tube method and charcoal tube method were used to collect and analyze samples (thermal desorption tube method %RDS = 1.9 for n = 6; charcoal tube method %RDS = 6.5 for n = 4). Results for both methods were compared and showed indoor benzene levels ranging between 1.2 and 72 ppbv. The charcoal tube method usually gave lower results than the thermal desorption method. Nevertheless, the difference observed in benzene levels from each method was not significant as determined by application of the Wilcoxon t-test to these data. Using the thermal desorption method, the range of toluene found in homes was 0.1-111 ppbv. A correlation between toluene and benzene levels suggested the same point source. The benzene and toluene content of the indoor air and the number of small engines stored in the attached garage was also correlated. There was no correlation found between the urinary biomarker concentrations and the level of benzene or toluene measured inside the homes in the summer.