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Background: Recurrence of deformity remains a concern when fusing the first tarsometatarsal joint for correction of hallux valgus (HV). A recently described construct adds an additional point of fixation from the plantar medial first metatarsal to the intermediate cuneiform. The purpose of this study was to determine the maintenance of correction of the first and second intermetatarsal angle, hallux valgus angle, and tibial sesamoid position after undergoing a first tarsometatarsal joint arthrodesis using the proposed construct., Methods: A radiographic review was performed of patients with HV treated with a first tarsometatarsal joint arthrodesis with the addition of a cross-screw intermediate cuneiform construct. Three observers reviewed radiographic data, including preoperative weightbearing, first weightbearing, and final weightbearing plain-film radiographs. Initial improvement and maintenance of intermetatarsal angle, hallux valgus angle (HVA), and tibial sesamoid position were evaluated radiographically. A total of 62 patients met inclusion criteria and were included in the study. Mean follow-up time was 9.3 months (SD 6.7)., Results: Bony union was achieved in 60 of 62 patients (96.7%). Two of 62 patients required revision surgery as a result of recurrence (3.3%). Final mean improvement of the intermetatarsal angle (IMA) was 6.8 degrees (±2.9 degrees), HVA was 14.8 degrees (±7.5 degrees), and tibial sesamoid position was 2.4 (±1.4) positions. Mean loss of IMA correction was 1.5 degrees (±1.6), HVA was 2.9 degrees (±4.8 degrees), and tibial sesamoid position was 0.8 (±0.8)., Conclusion: This study showed that the cross-screw intermediate cuneiform construct for first tarsometatarsal joint arthrodesis had a good union rate, a low complication rate, and maintained radiographic correction., Level of Evidence: Level IV, retrospective case series.

The Chronic Disease Self-Management Program (CDSMP) is an evidence-based program that is affective in managing chronic conditions and improving health outcomes in diverse populations; however, the program may not effectively reach the Deaf community. Deafness is associated with chronic health conditions and low health literacy, making a health education program such as CDSMP a good fit for this population. This study adapted and evaluated CDSMP in American Sign Language (ASL). The aims of this study were to (1) adapt the CDSMP curriculum for Deaf participants; (2) evaluate the program fidelity, participant satisfaction, and qualitative feedback; and (3) provide recommendations for improving the accessibility of CDSMP for the Deaf community. We evaluated the CDSMP program offered by lay leaders in ASL to Deaf participants. Program fidelity and participant satisfaction were high (93% and 88.9%, respectively). Qualitative feedback from participants and lay leaders informed implementation recommendations. Based on these findings, we offer 10 recommendations for offering CDSMP to the Deaf community. This study demonstrates that CDSMP can be successfully offered in ASL to Deaf participants with minimal adaptations. Offering CDSMP in ASL to accommodate Deaf learners promises to improve health outcomes in this vulnerable population.

Background: The purpose of this investigation was to compare the magnitude of rotatory knee laxity in patients with a partial anterior cruciate ligament (ACL) tear, those with a complete ACL tear, and those who had undergone a failed ACL reconstruction. It was hypothesized that rotatory knee laxity would increase with increasing injury grade, with knees with partial ACL tears demonstrating the lowest rotatory laxity and knees that had undergone failed ACL reconstruction demonstrating the highest rotatory laxity., Methods: A prospective multicenter study cohort of 354 patients who had undergone ACL reconstruction between 2012 and 2018 was examined. All patients had both injured and contralateral healthy knees evaluated using standardized, preoperative quantitative pivot shift testing, determined by a validated, image-based tablet software application and a surface-mounted accelerometer. Quantitative pivot shift was compared with the contralateral healthy knee in 20 patients with partial ACL tears, 257 patients with complete ACL tears, and 27 patients who had undergone a failed ACL reconstruction. Comparisons were made using 1-way analysis of variance (ANOVA) with post hoc 2-sample t tests with Bonferroni correction. Significance was set at p < 0.05., Results: There were stepwise increases in side-to-side differences in quantitative pivot shift in terms of lateral knee compartment translation for patients with partial ACL tears (mean [and standard deviation], 1.4 ± 1.5 mm), those with complete ACL tears (2.5 ± 2.1 mm), and those who had undergone failed ACL reconstruction (3.3 ± 1.9 mm) (p = 0.01) and increases in terms of lateral compartment acceleration for patients with partial ACL tears (0.7 ± 1.4 m/s), those with complete ACL tears (2.3 ± 3.1 m/s), and those who had undergone failed ACL reconstruction (2.4 ± 5.5 m/s) (p = 0.01). A significant difference in lateral knee compartment translation was found when comparing patients with partial ACL tears and those with complete ACL tears (1.2 ± 2.1 mm [95% confidence interval (CI), 0.2 to 2.1 mm]; p = 0.02) and patients with partial ACL tears and those who had undergone failed ACL reconstruction (1.9 ± 1.7 mm [95% CI, 0.8 to 2.9 mm]; p = 0.001), but not when comparing patients with complete ACL tears and those who had undergone failed ACL reconstruction (0.8 ± 2.1 [95% CI, -0.1 to 1.6 mm]; p = 0.09). Increased lateral compartment acceleration was found when comparing patients with partial ACL tears and those with complete ACL tears (1.5 ± 3.0 m/s [95% CI, 0.8 to 2.3 m/s]; p = 0.0002), but not when comparing patients with complete ACL tears and those who had undergone failed ACL reconstruction (0.1 ± 3.4 m/s [95% CI, -2.2 to 2.4 m/s]; p = 0.93) or patients with partial ACL tears and those who had undergone failed ACL reconstruction (1.7 ± 4.2 m/s [95% CI, -0.7 to 4.0 m/s]; p = 0.16). An increasing lateral compartment translation of the contralateral, ACL-healthy knee was found in patients with partial ACL tears (0.8 mm), those with complete ACL tears (1.2 mm), and those who had undergone failed ACL reconstruction (1.7 mm) (p < 0.05)., Conclusions: A progressive increase in rotatory knee laxity, defined by side-to-side differences in quantitative pivot shift, was observed in patients with partial ACL tears, those with complete ACL tears, and those who had undergone failed ACL reconstruction. These results may be helpful when assessing outcomes and considering indications for the management of high-grade rotatory knee laxity., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Severe foot and ankle deformities can be associated with high complication rates and impaired quality of life in patients. Surgical correction using a talectomy procedure has previously been described in many lower extremity pathologies and is a powerful tool for the correction of severe foot and ankle deformity. This study aimed to describe the role of talectomy and the outcomes of this procedure in patients presenting with severe foot and ankle deformity. A review of 45 patients undergoing talectomy by a single surgeon was completed. Data extracted included the cause of deformity, history of infection, body mass index, and relevant comorbidities. Outcome measures of interest were minor or major complications and limb functionality at final follow-up. Statistical analysis was performed by using a Wilcoxon rank sum test and a Fisher exact test looking at variables affecting selected outcome measures. Limb salvage occurred in 38 of 45 patients (84.4%). Patients with an infection history had 89% lower odds of a functional limb at final follow-up (p = .0389). Six of 7 patients (85.7%) who ultimately underwent amputation had a history of prior infection. Women had 8.25 times higher odds of having a functional limb compared with men (p = .047). All 13 patients with major complications had neuropathy (p = .024). Patients with chronic lower extremity deformities can successfully be treated with a talectomy as a part of the reconstructive procedure. This is a challenging patient population that is associated with a high complication rate. Patients with a history of infection should be counseled on the possibility of requiring major amputation., (Copyright © 2019. Published by Elsevier Inc.)

Background and Purpose : There is increasing interest among physical therapists from high-income countries to participate in education development projects in low-income countries. However, there are few examples in the literature of effective developmental models or projects. This case report describes a model for improving pediatric clinical decision making skills among Rwandan physical therapists using best practices in clinical decision making, evidence-based practice where possible, and use of the International Classification of Functioning and Disability (ICF) model. Case Description : A 48-hour continuing professional development course based on the pediatric section of the Advancement of Rwandan Rehabilitation Services Project (ARRSP) was presented to 66 Rwandan physical therapists in the form of classroom lectures, laboratory and case study practice, and clinical visits to the course participant's work place. Interactive teaching and learning was emphasized. Outcomes : Course participants completed a pre- and post-course assessment addressing course content. There was a 53% improvement in post-course assessment scores. A post-course evaluation eliciting participants' confidence in eight clinical decision making skills emphasized in course material was also administered. Comments were strongly positive (92%) for the value of clinical visits in reinforcing the participant's new clinical skills. Discussion : This case report documents a global health continuing professional development project that improved pediatric rehabilitation knowledge and clinical skill confidence. The project incorporated sustainability by soliciting both input and involvement of the target audience from start to finish; from the needs assessment to classroom teaching. Building on these two aspects promotes a sense of ownership and longevity.

Chronic deformity of the foot can lead to ulceration, infection, and amputation. Midfoot wedge osteotomy for deformity correction has been described in the literature; however, most reports are case review or small series. Wedge osteotomy can be performed from a medial or plantar approach, but there are limited data on outcomes regarding these relatively uncommon procedures. This study aims to review a population of patients with a rocker bottom foot deformity that underwent a midfoot wedge resection performed from the plantar surface for deformity correction, wound healing, and limb salvage. A review of medical records from a single foot and ankle surgeon was undertaken. Patients who had a midfoot wedge performed from the plantar surface to address rocker bottom deformity resulting from Charcot neuroarthropathy or severe flatfoot were included. Thirty patients met inclusion criteria. The outcome measures evaluated were minor and major complications, wound healing, and functional limb status. Statistical analysis was performed to evaluate factors that influenced outcomes. At time of final follow up, 17 of 20 (85%) preoperative wounds had healed. Mean preoperative talo-first metatarsal angle was -25° and improved to -5° postoperatively. An 87% limb salvage rate (26/30) was demonstrated. Body mass index was the only statistically significant factor that influenced functional limb status. Maintaining a functional limb can have profound effects on a patient's quality of life. Generally, patients with this severe rocker bottom foot deformity have multiple comorbidities and are at an increased risk of major amputation and early death. The current study has shown that patients with a rocker bottom foot deformity can benefit from midfoot wedge resection from a plantar approach to achieve a plantigrade foot., (Copyright © 2019 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Variants in the SLCO1B1 gene, encoding a hepatic methotrexate (MTX) transporter, affect clearance of high-dose MTX. We tested whether in the *14 and *15 alleles of SLCO1B1 influenced the response to low-dose MTX in juvenile idiopathic arthritis (JIA) patients., Methods: The study included 310 JIA patients genotyped for three single nucleotide polymorphisms (SNPs) in SLCO1B1 (rs4149056, rs2306283, and rs11045819). A patient's SLCO1B1 diplotype was determined by combining the SNPs into the *1a , *1b , *4 , *5 , *14 , and *15 alleles. Number of active joints at follow-up (visit closest to 6 months of treatment and prior to starting a tumor necrosis factor inhibitor) was used as the dependent variable in a negative binomial regression model that included active joint count at baseline as a covariate., Results: The SLCO1B1 * 14 allele was associated with less response to MTX (P = 0.024) and the *15 allele was not associated with response to MTX (P = 0.392)., Conclusion: SLCO1B1 alleles may be associated with poor response to MTX in JIA patients. The *14 allele has been associated with fast clearance (low exposure) after high-dose MTX in patients with leukemia. Thus, the SLCO1B1 gene may be informative for precision dosing of MTX in JIA patients. Patients carrying the *14 allele may require a higher dose than noncarriers to achieve a similar response to MTX., (© 2019 The Authors. ACR Open Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: The aim of this study was to compare the feasibility and effectiveness of neuromuscular electrical stimulation (NMES) with that of high-intensity volitional resistance training for improving muscle structure and function and physical function in patients with rheumatoid arthritis (RA). We also compared pre-intervention and post-intervention values of myocyte characteristics., Methods: In this 2-group, single-blind, randomized pilot study, adult patients with RA were assigned to 36 sessions of NMES (n = 31 patients) or volitional training (n = 28 patients) over 16 weeks. Outcome measures included muscle structure and function (quadriceps muscle area, density, and strength), physical function (performance-based and patient-reported), feasibility (increased pain, increased disease activity, attrition, and adherence), and myocyte characteristics (area, proportion of type I or II muscle fibers, and intramyocellular lipid content). Analysis of covariance was used to compare groups., Results: The intervention intensity in the NMES group was less than half that in the volitional exercise group (31% versus 77% of maximum effort). Both groups experienced significant improvements in muscle structure and function (P < 0.001 to 0.019). Improvements in muscle characteristics and physical function were not different between groups. Exercise did not result in serious adverse events or increases in pain and disease activity. Attrition was 29% in the NMES group and 7% in the volitional exercise group., Conclusion: Both NMES and high-intensity volitional resistance training can be used as effective approaches to improving muscle structure and function in patients with RA. NMES may be a viable alternative for improving muscle function in patients in whom high-intensity resistance exercise may not be tolerated or is contraindicated, but attrition must be considered when using this approach., (© 2018, American College of Rheumatology.)

People with disabilities (PWD) are more likely to use tobacco and less likely to access tobacco cessation programs compared with people without disabilities. Living Independent From Tobacco (LIFT), an evidence-based intervention designed for PWD, was piloted with dyads of PWD (n = 5) and their caregivers (n = 7). As an important source of practical and social support for PWD, caregivers also impact health-related attitudes, knowledge, and behaviors of PWD. Caregivers who smoke may unwittingly interfere with cessation efforts of the people they support. We found that LIFT could be offered to dyads of PWD and their caregivers with fidelity. The intervention was associated with increased use of coping strategies and self-efficacy to reduce smoking. Tobacco use decreased at post-test (-34.94%), with further reduction 6-months after the intervention (-50.60%). Implications for offering inclusive health promotion interventions to both PWD and their caregivers are discussed., Competing Interests: Declaration of Conflicting Interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The use of knotless suture anchors has increased in popularity; however, there is a paucity of literature examining the difference in clinical outcomes with traditional knotted fixation. It was hypothesized that knotless fixation would provide superior clinical outcomes, improved return to play (RTP), and lower revision rates as compared with traditional knotted fixation in the repair of SLAP IIb tears. Seventy-four athletes who underwent arthroscopic SLAP IIb repair with traditional (n = 42) and knotless anchors (n = 32) by a single surgeon were evaluated after a minimum 2-year follow. Demographic and surgical data, RTP, Kerlan-Jobe Orthopaedic Clinic (KJOC) score, American Shoulder and Elbow Surgeons (ASES) score, stability, strength, and pain scores were compared. Knotless anchors had slightly higher RTP (93.5% vs 90.2%, P = .94) and RTP at the same level (58.1% vs 53.7% P = .81) compared with knotted fixation, but the difference did not reach statistical significance. Knotless anchors were less likely to require revision surgery than traditional anchors (9% vs 17%, P = .50), but the difference was not statistically significant. When comparing knotless and traditional knotted suture anchor repair of type llb SLAP tears, knotless fixation required less revision surgery and had higher RTP, ASES, and KJOC scores; however, statistical significance was not achieved in this relatively small cohort., Competing Interests: Authors' Disclosure Statement: Dr. James P. Bradley receives royalties from Arthrex. His co-authors report no actual or potential conflict of interest in relation to this article.

We explored the relationship between memory performance and conscious knowledge (or awareness) of what has been learned in memory-impaired patients with hippocampal lesions or larger medial temporal lesions. Participants viewed familiar scenes or familiar scenes where a change had been introduced. Patients identified many fewer of the changes than controls. Across all of the scenes, controls preferentially directed their gaze toward the regions that had been changed whenever they had what we term robust knowledge about the change: They could identify that a change occurred, report what had changed, and indicate where the change occurred. Preferential looking did not occur when they were unaware of the change or had only partial knowledge about it. The patients, overall, did not direct their gaze toward the regions that had been changed, but on the few occasions when they had robust knowledge about the change they (like controls) did exhibit this effect. Patients did not exhibit this effect when they were unaware of the change or had partial knowledge. The findings support the idea that awareness of what has been learned is a key feature of hippocampus-dependent memory., Competing Interests: The authors declare no conflict of interest.

When individuals select the recently studied (and familiar) item in a multiple-choice memory test, they direct a greater proportion of viewing time toward the to-be-selected item when their choice is correct than when their choice is incorrect. Thus, for both correct and incorrect choices, individuals indicate that the chosen item is old, but viewing time nevertheless distinguishes between old and new items. What kind of memory supports this preferential viewing effect? We recorded eye movements while participants made three-alternative, forced-choice recognition memory judgments for scenes. In experiment 1 ( n = 30), the magnitude of the preferential viewing effect was strongly correlated with measures of conscious, declarative memory: recognition accuracy as well as the difference in confidence ratings and in response times for correct and incorrect choices. In four analyses that minimized the contribution of declarative memory in order to detect a possible contribution from other processes, the preferential viewing effect was absent. In experiment 2, five memory-impaired patients with medial temporal lobe lesions exhibited a diminished preferential viewing effect. These patients also exhibited poor recognition accuracy and reduced differences in confidence ratings and response times for correct and incorrect choices. We propose that the preferential viewing effect is a phenomenon of conscious, declarative memory and is dependent on the medial temporal lobe. The findings support the link between medial temporal lobe function and declarative memory. When the effects of experience depend on the medial temporal lobe, the effects reflect conscious memory., Competing Interests: The authors declare no conflict of interest.

Understanding the nature of the magnetic-field-induced precipitation behaviors represents a major step forward towards unravelling the real nature of interesting phenomena in Fe-based alloys and especially towards solving the key materials problem for the development of fusion energy. Experimental results indicate that the applied high magnetic field effectively promotes the precipitation of M 23 C 6 carbides. We build an integrated method, which breaks through the limitations of zero temperature and zero external field, to concentrate on the dependence of the stability induced by the magnetic effect, excluding the thermal effect. We investigate the intimate relationship between the external field and the origins of various magnetics structural characteristics, which are derived from the interactions among the various Wyckoff sites of iron atoms, antiparallel spin of chromium and Fe-C bond distances. The high-magnetic-field-induced exchange coupling increases with the strength of the external field, which then causes an increase in the parallel magnetic moment. The stability of the alloy carbide M 23 C 6 is more dependent on external field effects than thermal effects, whereas that of M 2 C, M 3 C and M 7 C 3 is mainly determined by thermal effects.

It is well established that patients with memory impairment have more difficulty retrieving memories from the recent past relative to the remote past and that damage to the medial temporal lobe (MTL) plays a key role in this pattern of impairment. The precise role of the MTL and how it may interact with other brain regions remains an area of active research. We investigated the role of structures in a memory network that supports remembering. Our chapter focuses on two types of memory: episodic memory and semantic memory. Findings from studies of patients with brain damage and neuroimaging studies in patients and healthy individuals were considered together to identify the functional and structural neuroanatomy of past remembrance.

Eye movements can reflect memory. For example, participants make fewer fixations and sample fewer regions when viewing old versus new scenes (the repetition effect). It is unclear whether the repetition effect requires that participants have knowledge (awareness) of the old-new status of the scenes or if it can occur independent of knowledge about old-new status. It is also unclear whether the repetition effect is hippocampus-dependent or hippocampus-independent. A complication is that testing conscious memory for the scenes might interfere with the expression of unconscious (unaware), experience-dependent eye movements. In experiment 1, 75 volunteers freely viewed old and new scenes without knowledge that memory for the scenes would later be tested. Participants then made memory judgments and confidence judgments for each scene during a surprise recognition memory test. Participants exhibited the repetition effect regardless of the accuracy or confidence associated with their memory judgments (i.e., the repetition effect was independent of their awareness of the old-new status of each scene). In experiment 2, five memory-impaired patients with medial temporal lobe damage and six controls also viewed old and new scenes without expectation of memory testing. Both groups exhibited the repetition effect, even though the patients were impaired at recognizing which scenes were old and which were new. Thus, when participants viewed scenes without expectation of memory testing, eye movements associated with old and new scenes reflected unconscious, hippocampus-independent memory. These findings are consistent with the formulation that, when memory is expressed independent of awareness, memory is hippocampus-independent., (Published by Cold Spring Harbor Laboratory Press.)

An essential aspect of genetically-engineered mice (GEM) is the ability to produce live animals after the appropriate injection procedure. Animals are produced by implantation of manipulated embryos into pseudopregnant females for gestation, parturition, and growth to the weaning stage. This study was carried out to test whether the anesthesia used during surgery could affect the number of pups produced. Anesthetics commonly used for implant surgery include tribromoethanol (Avertin) delivered by intraperitoneal (IP) injection, IP-injected ketamine:xylazine or ketamine:medetomidine mix, and inhaled isoflurane. To determine if the anesthesia used might affect the number of animals produced, each anesthetic agent was tested in implant surgeries and the numbers of pups produced using both wild-type and GEM embryos were assessed. Parallel studies were conducted in institutions in the EU and in the USA. Based on a direct comparison of pregnancy status, number of pups born, and number of pups weaned for each agent, we found no statistical differences among the three anesthetics. We conclude that all three anesthetic agents tested are equally useful for implantation surgery., (© The Author(s) 2015.)

Recent studies have asked whether activity in the medial temporal lobe (MTL) and the neocortex can distinguish true memory from false memory. A frequent complication has been that the confidence associated with correct memory judgments (true memory) is typically higher than the confidence associated with incorrect memory judgments (false memory). Accordingly, it has often been difficult to know whether a finding is related to memory confidence or memory accuracy. In the current study, participants made recognition memory judgments with confidence ratings in response to previously studied scenes and novel scenes. The left hippocampus and 16 other brain regions distinguished true and false memories when confidence ratings were different for the two conditions. Only three regions (all in the parietal cortex) distinguished true and false memories when confidence ratings were equated. These findings illustrate the utility of taking confidence ratings into account when identifying brain regions associated with true and false memories. Neural correlates of true and false memories are most easily interpreted when confidence ratings are similar for the two kinds of memories., (Published by Cold Spring Harbor Laboratory Press.)

Objective: The study characterized the status of retrograde amnesia (RA) in amnestic mild cognitive impairment (MCI)., Method: We measured RA, anterograde amnesia (AA), brain measures, apolipoprotein-E status (ApoE), and conversion to probable Alzheimer's disease (AD) across 3 years in 15 individuals with MCI. We compared the severity of amnesia and brain atrophy in MCI to a group of patients with limited damage to the hippocampus (H) or more extensive damage to the medial temporal lobe (MTL)., Results: The MCI group exhibited modest AA, together with severe RA, covering nearly 4 decades before their diagnosis. Compared with H-MTL patients, the temporal extent of RA was disproportionate to the severity of AA. The MCI group exhibited more modest AA and MTL atrophy than H-MTL patients, together with more severe RA and neocortical atrophy than H-MTL patients. The severity of AA corresponded to the integrity of MTL structures, whereas the severity of RA corresponded to the integrity of both MTL and neocortical structures. RA (but not AA, nor measures of cognitive status) was related to ApoE status and subsequent diagnosis of probable AD. RA was predicted by heritable risk for AD, in addition to the integrity of MTL and neocortical structures., Conclusions: Compared with H-MTL patients, the MCI group exhibited RA that was disproportionate to their AA and that was more severe than would be expected if their atrophy were limited primarily to the MTL. Heritable risk for AD, as well as the integrity of brain regions within and beyond the MTL, are important for understanding RA in MCI., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

Tyrosinase is the rate-limiting enzyme for the production of melanin pigmentation. In the mouse and other animals, homozygous null mutations in the Tyrosinase gene (Tyr) result in the absence of pigmentation, i.e. albinism. Here we used the CRISPR/Cas9 system to generate mono- and bi-allelic null mutations in the Tyr locus by zygote injection of two single-guide and Cas9 RNAs. Injection into C57BL/6N wild-type embryos resulted in one completely albino founder carrying two different Tyr mutations. In addition, three pigmentation mosaics and fully pigmented littermates were obtained that transmitted new mutant Tyr alleles to progeny in test crosses with albinos. Injection into Tyr heterozygous (B6CBAF1/J×FVB/NJ) zygotes resulted in the generation of numerous albinos and also mice with a graded range of albino mosaicism. Deep sequencing revealed that the majority of the albinos and the mosaics had more than two new mutant alleles. These visual phenotypes and molecular genotypes highlight the somatic mosaicism and allele complexity in founders that occurs for targeted genes during CRISPR/Cas9-mediated mutagenesis by zygote injection in mice., (Copyright © 2014. Published by Elsevier Inc.)

Hippocampal damage has been thought to result in broad memory impairment. Recent studies in humans, however, have raised the possibility that recognition memory for faces might be spared. In five experiments we investigated face recognition in patients with hippocampal lesions (H) or large medial temporal lobe (MTL) lesions, including patients where neurohistological information was available. Recognition of novel faces was unequivocally intact in H patients but only at a short retention interval. Recognition memory for words, buildings, inverted faces, and famous faces was impaired. For MTL patients, recognition memory was impaired for all materials and across all retention intervals. These results indicate that structures other than the hippocampus, perhaps the perirhinal cortex, can support face recognition memory in H patients under some conditions. The fact that the faces were novel when recognition memory was intact does not fully account for our findings. We propose that the role of the hippocampus in recognition memory is related to how recognition decisions are accomplished. In typical recognition tasks, participants proceed by forming an association between a study item and the study list, and the recognition decision is later made based on whether participants believe the item was on the study list. We suggest that face recognition is an exception to this principle and that, at short retention intervals, participants can make their recognition decisions without making explicit reference to the study list. Important features of faces that might make face recognition exceptional are that they are processed holistically and are difficult to verbally label.

Declarative memory for rapidly learned, novel associations is thought to depend on structures in the medial temporal lobe (MTL), whereas associations learned more gradually can sometimes be supported by nondeclarative memory and by structures outside the MTL. A recent study suggested that even rapidly learned associations can be supported by structures outside the MTL when an incidental encoding procedure termed "fast mapping" (FM) is used. We tested six memory-impaired patients with bilateral damage to hippocampus and one patient with large bilateral lesions of the MTL. Participants saw photographs and names of animals, plants, and foods that were previously unfamiliar (e.g., mangosteen). Instead of asking participants to study name-object pairings for a later memory test (as with traditional memory instructions), participants answered questions that allowed them to infer which object corresponded to a particular name. In a second condition, participants learned name-object associations of unfamiliar items by using standard, explicit encoding instructions (e.g., remember the mangosteen). In FM and explicit encoding conditions, patients were impaired (and performed no better than a group that was given the same tests but had not previously studied the material). The same results were obtained in a second experiment that used the same procedures with modifications to allow for more robust learning and more reliable measures of performance. Thus, our results with the FM procedure and memory-impaired patients yielded the same deficits in learning and memory that have been obtained by using other more traditional paradigms.

The study of anterograde and retrograde amnesia (AA and RA) in the laboratory and the clinic has provided important information about the structure and organization of memory. The severity of AA is usually correlated with the severity of RA. Nevertheless, variations in the expression of AA and RA have been reported, which presumably reflect variation in the locus and extent of brain damage. The relationship between AA and RA has rarely been described quantitatively in groups of patients where detailed anatomical information is available. We have quantified the severity of AA and RA for factual information in 11 memory-impaired patients with bilateral medial temporal lobe lesions, including 5 for whom detailed post-mortem neurohistological information was available. The findings describe an orderly relationship between AA and RA, such that patients with more severe AA also had more extensive RA. In addition, RA was measurable only after AA reached a substantial level of severity. This relationship between AA and RA in patients with identified medial temporal lobe lesions appears to describe a general principle, which applies to a range of etiologies, including traumatic amnesia, where the locus and extent of brain damage is less well understood. Whenever patients deviate substantially from the relationship described here, one should be alert to the likelihood that significant damage has occurred outside or in addition to the structures in the medial temporal lobe., (© 2013 Published by Elsevier Ltd.)

Background: Clinical communication is recognized as a major source of errors in hospitals. The lack of documentation of communication, especially among verbal interactions, often creates hindrances and impedes improvement efforts. By providing smartphones to residents and encouraging nurses to communicate with residents by email shifted much of the communication to emails which permitted analysis of content., Objective: Description on the interprofessional email communication between doctors and nurses occurring on the general internal medicine wards at two academic hospitals., Design: A prospective analysis of email communications between doctors and nurses., Setting: 34 out of the 67 residents who were on the general medicine clinical teaching units consented to allow analysis of their emails over a 6 month period., Main Measures: Statistical tabulations were performed on the volume and frequency of communications as well the response time of messages. Two physicians coded the content of randomly selected emails for urgency, emotion, language, type of interaction, and subject content., Key Results: A total of 13,717 emails were available for analysis. Among the emails from nurses, 39.1% were requests for a call back, 18.9% were requests for a response by email and the remaining 42.0% indicated no response was required from physicians. For the messages requesting a response by email, only 50% received an email response. Email responses had a median response time of 2.3 minutes. Content analysis revealed that messages were predominantly non-urgent. The two most frequent purposes for communications were to convey information (91%) and to request action by the physician (36%)., Conclusions: A smartphone-based email system facilitated the description and content analysis of a large amount of email communication between physicians and nurses. Our findings provide a picture of the communication between physicians, nurses and other healthcare professionals. This work may help inform the further development of information and communications technology that can improve clinical communication.

Recognition memory is thought to consist of two component processes--recollection and familiarity. It has been suggested that the hippocampus supports recollection, while adjacent cortex supports familiarity. However, the qualitative experiences of recollection and familiarity are typically confounded with a quantitative difference in memory strength (recollection > familiarity). Thus, the question remains whether the hippocampus might in fact support familiarity-based memories whenever they are as strong as recollection-based memories. We addressed this problem in a novel way by using the Remember/Know procedure, which allowed us to explicitly match the confidence and accuracy of Remember and Know decisions. As in earlier studies, recollected items had higher accuracy and confidence than familiar items, and hippocampal activity was higher for recollected items than for familiar items. Furthermore, hippocampal activity was similar for familiar items, misses, and correct rejections. When the accuracy and confidence of recollected and familiar items were matched, the findings were dramatically different. Hippocampal activity was now similar for recollected and familiar items. Importantly, hippocampal activity was also greater for familiar items than for misses or correct rejections (as well as for recollected items vs misses or correct rejections). Our findings suggest that the hippocampus supports both recollection and familiarity when memories are strong.

Findings from functional MRI (fMRI) studies of recognition memory and the medial temporal lobe often suggest qualitative differences in the contribution of the hippocampus and perirhinal cortex. This interpretation is complicated by the fact that most of the methods intended to demonstrate qualitative differences also separate strong memories from weak memories. Thus, apparent qualitative differences might reflect quantitative differences in how measured activity in medial temporal lobe structures varies with memory strength. We tested the hypothesis that the relationship between activity at the time of study and subsequent memory strength is nonlinear in hippocampus and perirhinal cortex and also distinctly different in those two structures. We found that activity in the hippocampus was characterized by a positively accelerated function and that activity in the perirhinal cortex was associated with a statistically different, negatively accelerated function. Our results do not count against the possibility that these structures differ qualitatively in their contributions to memory. Rather, our findings show how an alternative interpretation based on quantitative differences can also account for a good deal of data, and they suggest that a demonstration of qualitative differences requires more stringent criteria than are achieved in most fMRI studies.

Since an automobile accident in 2005, patient FL has reported difficulty retaining information from one day to the next. During the course of any given day, she describes her memory as normal. However, memory for each day disappears during a night of sleep. She reports good memory for events that occurred before the accident. Although this pattern of memory impairment is, to our knowledge, unique to the medical literature, it was depicted in the fictional film "50 First Dates". On formal testing, FL performed moderately well when trying to remember material that she had learned during the same day, but she exhibited no memory at all for material that she knew had been presented on a previous day. For some tests, unbeknownst to FL, material learned on the previous day was intermixed with material learned on the same day as the test. On these occasions, FL's memory was good. Thus, she was able to remember events from earlier days when memory was tested covertly. FL performed differently in a number of ways from individuals who were instructed to consciously feign her pattern of memory impairment. It was also the impression of those who worked with FL that she believed she had the memory impairment that she described and that she was not intentionally feigning amnesia. On the basis of her neuropsychological findings, together with a normal neurological exam, normal MRI findings, and psychiatric evaluation, we suggest that FL exhibits a unique form of functional amnesia and that its characterization may have been influenced by knowledge of how amnesia was depicted in a popular film. She subsequently improved (and began retaining day-to-day memory) at Johns Hopkins University where she was in a supportive in-patient environment and was shown how to take control of her condition by interrupting her sleep at 4-h intervals., (Published by Elsevier Ltd.)

We measured brain activity using event-related fMRI as participants recalled answers to 160 questions about news events that had occurred during the past 30 years. Guided by earlier findings from patients with damage limited to the hippocampus who were given the same test material, we looked for regions that exhibited gradually decreasing activity as participants recalled memories from 1-12 years ago and a constant level of activity during recall of more remote memories. Regions in the medial temporal lobe exhibited a decrease in brain activity in relation to the age of the memory (hippocampus, temporopolar cortex, and amygdala). Regions in the frontal lobe, temporal lobe, and parietal lobe exhibited the opposite pattern. The findings for all of these regions were unrelated to the richness of the memories, to how well test questions were remembered later (encoding for subsequent memory), nor to how frequently semantic memories were accompanied by personal, episodic recollections. Last, activity in a different group of regions (perirhinal cortex, parahippocampal cortex, and inferior temporal gyrus) was associated with how well the test questions were subsequently remembered. The results support the idea that medial temporal lobe structures play a time-limited role in semantic memory.

We investigated the relationship between experience-dependent eye movements, hippocampus-dependent memory, and aware memory. We measured eye movements in young adults, older adults, and memory-impaired patients with damage to the medial temporal lobe as they viewed 120 novel scenes and 120 previously viewed scenes. Participants indicated if each scene was old or new and also gave a confidence rating for the memory judgment. Young adults and older adults explored old scenes less than they explored new scenes, but the patients did not. For the young and older adults, this effect was observed only when participants were aware of the scene's familiar or novel status. In a second experiment, young adults viewed scenes that were either new, had been viewed previously, or had been viewed previously but had been changed (i.e., an object within the scene was either added or removed). The only instructions were to pay attention to the scenes and view each scene as it appeared, and there was no expectation that memory would be tested. Directly after the first altered scene was presented, participants were asked to classify the scene as new, old, or old but changed. Participants who were aware of the manipulation preferentially viewed the changed region, but participants who were unaware did not. These findings suggest that experience-dependent eye movements reflect hippocampus-dependent (and aware) memory, even when participants have no expectation that memory is being tested; and they are consistent with the view that awareness of what is learned is a fundamental characteristic of hippocampus-dependent memory.

The initial learning and subsequent behavioral expression of fear are often viewed as independent processes with potentially unique neural substrates. Laboratory animal studies of Pavlovian fear conditioning suggest that the amygdala is important for both forming stimulus associations and for subsequently expressing learned behavioral responses. In the present article, human amygdala activity was studied during the autonomic expression of conditional fear in two differential conditioning experiments with event-related functional magnetic resonance imaging and concurrent recording of skin conductance responses (SCRs). Trials were classified on the basis of individual participants' SCRs. Significant amygdala responding was detected only during trials on which a signal both predicted shock and elicited significant conditional SCR. Conditional stimulus presentation or autonomic activity alone was not sufficient. These results indicate that amygdala activity may specifically reflect the expression of learned fear responses and support the position that this region plays a central role in the expression of emotional reactions., (2006 APA, all rights reserved)

We asked what kind of memory is operating when eye movements change as the result of experience. Participants viewed scenes that were either novel, repeated, or manipulated (i.e., a change was introduced in one region of the scene). Eye movements differed depending on the past viewing history of each scene. Participants made fewer fixations and sampled fewer regions when scenes were repeated than when scenes were novel. When scenes were altered, participants made more fixations in the altered region, spent more time looking at the altered region, and made more transitions into and out of the altered region than in unchanged (matched) regions in the repeated scenes. Importantly, these effects occurred only when individuals were aware that a change had occurred. Participants who were unaware that the scene had been altered looked at the changed scenes in the same way that they looked at repeated scenes. Thus, there was no indication that eye movements could reveal an unaware (unconscious) form of memory. Instead, eye movements reflected conscious memory of whether the scene was repeated or manipulated. The findings were the same when awareness was assessed after viewing all the scenes (experiment 1) and when awareness was assessed after each scene was presented (experiment 2). In experiment 3, memory-impaired patients with damage limited to the hippocampus were impaired at deciding whether scenes were novel, repeated, or manipulated. Thus, the ability to consciously recollect recent encounters with scenes reflects a form of hippocampus-dependent memory. The findings show that experience-dependent eye movements in response to altered scenes reflect conscious, declarative memory, and they support the link between aware memory, declarative memory, and hippocampus-dependent memory.

We studied item and source memory with fMRI in healthy volunteers and carried out a parallel study in memory-impaired patients. In experiment 1, volunteers studied a list of words in the scanner and later took an item memory test and a source memory test. Brain activity in the hippocampal region, perirhinal cortex, and parahippocampal cortex was associated with words that would later be remembered (item memory). The activity in these regions that predicted subsequent success at item memory predicted subsequent source memory to a similar degree. In experiment 2, memory-impaired patients with damage thought to be limited to the hippocampal region were given an item memory test and a source memory test, as in experiment 1. The patients were similarly impaired on the item memory test and the source memory test. Together, the findings suggest that medial temporal lobe structures broadly support recognition memory function and that item memory and source memory similarly depend on these structures.

The production of chimeric mice is a complex process, requiring the careful coordination of tissue culture cell growth, production of a large number (30-75) of competent blastocysts and the availability of appropriately timed pseudo pregnant female mice. Failure at any of these steps can impinge upon the rapid production of chimeras. One potential improvement for the efficient generation of chimeric mice would be the utilization of cryopreserved embryos suitable for injection. C57Bl/6 morulae were frozen using a standard 2-step protocol with ethylene glycol as the cryopreservation agent. We determined that cryopreserved morulae could thaw, culture to blastocyst stage in KSOM media and survive injection at rates equivalent to control embryos. Cryopreserved morulae were also equivalent to controls at all later stages in the process of production of chimeric mice, including birth rate, percentage chimerism of resulting animals and ability to produce germline progeny. Hence, cryopreservation of morulae for blastocyst injection is a suitable option to enhance the efficiency of chimeric mouse generation.

Biocide chemicals are commonly used as preservatives for cosmetic and personal care products and the conditions for their use are stipulated in Annex VI of the Cosmetics Directive. In these studies the cytotoxicity (EC50 and EC90) of a range of preservatives including the isothiazolinone family, formaldehyde donors, parabens mixtures and organic acids have been established in the Balb/C 3T3 clone A31 fibroblast cell-line following a 1h exposure. Cell viability was established using the neutral red uptake assay 24h after exposure. The potency of the preservatives spanned several orders of magnitude from the isothiazolinones (EC50<10ppm) to the organic acids (EC50>10,000ppm). Although these values are directly proportional to the anti-microbial efficacy of the actives, they do not reflect the addition levels commonly used to preserve formulations, which are intended to provide prolonged protection against a wide spectrum of spoilage organisms. In a further study, the cytotoxic profile of an unpreserved standard rinse-off body wash formulation was assessed. Two concentrations of the formulation were selected: 0.1% v/v (EC98) and 0.15% v/v (EC82) to study the effects of selected preservative chemicals at recommended addition levels upon the cytotoxicity of the formulation. At 0.1%, only preservation with benzoate/sorbate at the highest addition level increased the toxicity, whereas at 0.15%, preservation with 2-bromo-2-nitro-propane-1,3-diol increased the cytotoxicity of the formulation. No other preservatives, including isothiazolinones and formaldehyde donors affected the basal cytotoxicity of the formulation. Theses studies have provided a standardised assessment of the cytotoxicity of cosmetic preservatives and demonstrated that preservation of a rinse-off formulation at recommended addition levels is unlikely to affect the cytotoxic profile.

There has been debate about whether differential delay eyeblink conditioning can be acquired without awareness of the stimulus contingencies. In 4 experiments, the authors reexamined this question. Older participants were tested with a tone and white noise (Experiment 1) or with 2 tones (Experiment 2). In addition, younger participants were tested with 2 tones (Experiment 3) or with 2 tones plus the parameters from an earlier study that had reported a relationship between conditioning and awareness (Experiment 4). Participants who were designated aware of the stimulus contingencies and participants who were designated unaware exhibited equivalent levels of differential eyeblink conditioning. Awareness of stimulus contingencies is not required for differential delay eyeblink conditioning when simple conditioned stimuli are used., (Copyright 2005 APA.)

Previous functional magnetic resonance imaging (fMRI) studies have characterized brain systems involved in conditional response acquisition during Pavlovian fear conditioning. However, the functional neuroanatomy underlying the extinction of human conditional fear remains largely undetermined. The present study used fMRI to examine brain activity during acquisition and extinction of fear conditioning. During the acquisition phase, participants were either exposed to light (CS) presentations that signaled a brief electrical stimulation (paired group) or received light presentations that did not serve as a warning signal (control group). During the extinction phase, half of the paired group subjects continued to receive the same treatment, whereas the remainder received light alone. Control subjects also received light alone during the extinction phase. Changes in metabolic activity within the amygdala and hippocampus support the involvement of these regions in each of the procedural phases of fear conditioning. Hippocampal activity developed during acquisition of the fear response. Amygdala activity increased whenever experimental contingencies were altered, suggesting that this region is involved in processing changes in environmental relationships. The present data show learning-related amygdala and hippocampal activity during human Pavlovian fear conditioning and suggest that the amygdala is particularly important for forming new associations as relationships between stimuli change.

Previous functional magnetic resonance imaging (fMRI) studies with human subjects have explored the neural substrates involved in forming associations in Pavlovian fear conditioning. Most of these studies used delay procedures, in which the conditioned stimulus (CS) and unconditioned stimulus (UCS) coterminate. Less is known about brain regions that support trace conditioning, a procedure in which an interval of time (trace interval) elapses between CS termination and UCS onset. Previous work suggests significant overlap in the neural circuitry supporting delay and trace fear conditioning, although trace conditioning requires recruitment of additional brain regions. In the present event-related fMRI study, skin conductance and continuous measures of UCS expectancy were recorded concurrently with whole-brain blood oxygenation level-dependent (BOLD) imaging during direct comparison of delay and trace discrimination learning. Significant activation was observed within the visual cortex for all CSs. Anterior cingulate and medial thalamic activity reflected associative learning common to both delay and trace procedures. Activations within the supplementary motor area (SMA), frontal operculum, middle frontal gyri, and inferior parietal lobule were specifically associated with trace interval processing. The hippocampus displayed BOLD signal increases early in training during all conditions; however, differences were observed in hippocampal response magnitude related to the accuracy of predicting UCS presentations. These results demonstrate overlapping patterns of activation within the anterior cingulate, medial thalamus, and visual cortex during delay and trace procedures, with additional recruitment of the hippocampus, SMA, frontal operculum, middle frontal gyrus, and inferior parietal lobule during trace conditioning. These data suggest that the hippocampus codes temporal information during trace conditioning, whereas brain regions supporting working memory processes maintain the CS-UCS representation during the trace interval.

Although laboratory animal studies have shown that the amygdala plays multiple roles in conditional fear, less is known about the human amygdala. Human subjects were trained in a Pavlovian fear conditioning paradigm during functional magnetic resonance imaging (fMRI). Brain activity maps correlated with reference waveforms representing the temporal pattern of visual conditional stimuli (CSs) and subject-derived autonomic responses were compared. Subjects receiving paired CS-shock presentations showed greater amygdala activity than subjects receiving unpaired CS-shock presentations when their brain activity was correlated with a waveform generated from their behavioral responses. Stimulus-based waveforms revealed learning differences in the visual cortex, but not in the amygdala. These data support the view that the amygdala is important for the expression of learned behavioral responses during Pavlovian fear conditioning.

The predictions from MEAD, a model that simulates the transport of radionuclides in the marine environment, are presented for the Irish Sea. MEAD predictions for (137)Cs and Pu(alpha) are presented following discharges from BNFL Sellafield and the predictions compared to measured data from near the discharge location and further a field in the Irish Sea. The model performs well in most circumstances given the uncertainties involved in both modelling and data collection although some inconsistencies in the predictions are found. MEAD is also compared to other models of radionuclide transport in the Irish Sea.

A mathematical model (MEAD) that simulates the transport of radioactivity in shelf-sea environments is presented. In the model it is assumed that the radioactivity can be present in three phases and transport both within and between the phases is captured. The set-up of the model for the Irish Sea is described and results from a simple discharge scenario are presented for (137)Cs and (239)Pu. From these results it appears that MEAD provides a good representation of the transport of radionuclides in the Irish Sea.

In vivo experiments have shown that melanocytes are more sensitive than keratinocytes to the cytotoxic effects of sulfur mustard when it is applied topically to pig skin.1 It has been hypothesized that this is caused by the uncoupling of the melanogenic pathway by depletion of cellular glutathione, resulting in the uncontrolled production of cytotoxic quinone free-radical species by tyrosinase.2. In the present study, the feasibility of blocking the melanogenic pathway as a means of reducing the cytotoxicity of sulfur mustard was evaluated using kojic acid. Kojic acid is a topically applied depigmenting agent that exerts its effect by acting as a slow-binding, competitive inhibitor of tyrosinase.3 Preincubation of G361 pigmented melanoma cells and mixed cultures of G361 cells and SVK keratinocytes with 2.5 mM kojic acid resulted in significant increases in the viability of these cultures as determined by neutral red (NR) and gentian violet (GV) dye binding assays for up to 48 h following exposure to 50 microM sulfur mustard. The highest levels of protection were seen in the G361 cultures, with a 26.8% increase in culture viability (NR assay) compared with the sulfur-mustard-only controls at 24 h. Preincubation of SVK cells alone with kojic acid resulted in lower increases in viability (2.5% at 24 h by the NR assay). Inhibition of the melanogenic pathway reduces the sensitivity of cultures containing pigment cells to sulfur mustard.

In vivo, the pigment producing melanocytes are the most susceptible cell type to sulphur mustard (HD) in the epidermal region of pig skin. It has been postulated that this is due to the melanogenic pathway producing a cytotoxic, free radical cascade within the melanocyte following HD poisoning, leading to cellular necrosis and subsequent inflammation. To test this hypothesis, the cytotoxicity of HD was tested in three human melanoma cell lines and compared to SVK-14 human keratinocytes, a cell line in which the response to HD has already been characterised. The results of both neutral red (NR) and gentian violet (GV) assays showed that all three melanoma cell lines, particularly the G361 line, were less susceptible to the toxic effects of HD than the SVK-14 keratinocyte cell line. Preliminary data indicate that the expression level of the DNA repair cofactor, proliferating cell nuclear antigen (PCNA), is up to 13-fold greater in the HD-resistant cell line G361 compared to the HD-sensitive SVK-14 cell line. The data point to the importance of DNA lesions in HD-induced cell death and to potential mechanisms associated with increased resistance to HD. A dose-response study was carried out to confirm the differences between these two cell lines. It was found that the G361 line is 5-fold more resistant to HD and 5.5-fold more resistant to the cytotoxic effects of H2O2 than the SVK-14 line, as determined by the MTT assay. The results suggest that differences in the relative efficiency of DNA repair processes may underlie these responses. Whilst the study indicates the limitations of using melanoma cell lines (in vitro) to model melanocyte responses to HD, analysis of the biochemical basis of the observed differences in sensitivity to HD could assist in the identification of novel therapeutic strategies against HD.

Epidermal melanocytes have a higher sensitivity to sulphur mustard (HD) compared with other skin cell types. This may be due to the enzymatic production of melanin precursors exerting an additional cytotoxic effect following HD depletion of the cellular protectant, GSH. Stimulation of the protein kinase C pathway in melanocytes is known to increase melanin production in melanocytes and melanoma cell lines. In order to investigate the role of pigment synthesis in HD toxicology, cultures of an unpigmented melanoma cell line (C32) and of a pigmented melanoma line (G361) were treated with the potent diacyl glycerol analogue, oleoyl acetyl glycerol (OAG), in order to determine if protein kinase C-mediated increases in pigment production could increase sensitivity to subsequent HD exposure. Stimulation of C32 cells with OAG exerted a significant protective effect against the cytotoxic effects of HD. However, this was not due to increased melanin synthesis because this cell line cannot synthesize melanin pigments. The protective action observed is postulated to be due to modulation of protein kinase C activity. In contrast, stimulation of G361 melanoma cells with OAG resulted in an increased level of cytotoxicity upon subsequent exposure to HD. Protein kinase C controls several cellular pathways including checkpoints in the cell cycle, stalling the cell in G and promoting transition through the G2/M boundary. Given the genotoxic properties of HD, these two points in the cell cycle are important in determining the overall cytotoxic effect of HD. Control of the cell cycle by protein kinase C modulation and manipulation of melanin synthetic pathways may have therapeutic benefits.

A mathematical model is presented that simulates the annually averaged transport of radionuclides, originating from the BNFL reprocessing plant at Sellafield, throughout the Irish Sea. The model, CUMBRIA77, represents the processes of radionuclide transport and dispersion in the marine environment and allows predictions of radionuclide concentration in various environmental media, including biota, to be made throughout the whole of the Irish Sea. In this paper we describe the use of the model to reconstruct the historical activity concentrations of 137Cs and 239+240Pu in a variety of environmental media in the western Irish Sea and along the Irish east coast back to 1950. This reconstruction exercise is of interest because only limited measurements of 137Cs and 239+240Pu activity are available prior to the 1980s. The predictions were compared to the available measured data to validate their accuracy. The results of the reconstruction indicate that activity concentrations of 137Cs in the western Irish Sea follow a similar, though slightly delayed and smoothed, profile to the discharges from the Sellafield site, with concentrations at the time of peak discharge (the mid-1970s) being around an order of magnitude higher than those measured in the 1980s and 1990s. By contrast, the concentrations of 239+240Pu at the time of peak discharges were similar to those presently measured. These differences reflect the distinct marine chemistries of the two nuclides, in particular the higher propensity of plutonium to bind to sediments leading to extended transport times. Despite these differences in behaviour the doses to Irish seafood consumers from 137Cs remain significantly higher than those from 239+240Pu.

Mammalian cells produce both N-arachidonoylethanolamine (20:4n-6 NAE, anandamide) and 2-arachidonoylglycerol (2-AG), lipid signaling molecules that activate cannabinoid receptors. Because both agonists occur in the presence of receptor-inactive congeners, we have developed a sensitive method for the simultaneous assay of N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAG). These lipid classes are isolated from total lipids by solid phase extraction and converted to tert-butyldimethylsilyl (tBDMS) derivatives in the presence of deuterated analogs. The tBDMS derivatives are analyzed by gas chromatography/mass spectrometry using selected ion monitoring programs specific for NAE and 2-MAG. Individual NAEs and 2-MAGs can be quantified in the nanogram and subnanogram range. The NAE and 2-MAG compositions of rat organs and cultured JB6 cells are reported.

fMRI was used to study human brain activity during Pavlovian fear conditioning. Subjects were exposed to lights that either signaled painful electrical stimulation (CS+), or that did not serve as a warning signal (CS-). Unique patterns of activation developed within anterior cingulate and visual cortices as learning progressed. Training with the CS+ increased active tissue volume and shifted the timing of peak fMRI signal toward CS onset within the anterior cingulate. Within the visual cortex, active tissue volume increased with repeated CS+ presentations, while cross-correlation between the functional time course and CS- presentations decreased. This study demonstrates plasticity of anterior cingulate and visual cortices as a function of learning, and implicates these regions as components of a functional circuit activated in human fear conditioning.

Existing drinking water wells are widely used for the collection of ground water samples to evaluate chemical contamination. A well comparison study was conducted to compare pesticide and nitrate-N data from specially designed stainless steel research monitoring wells with data from nearby existing on-farm drinking water wells. Results could help to determine whether adequate information concerning ground water contamination can be obtained from existing drinking water wells for use in making pollutant control decisions. The study was conducted during 1993-1994 in the Little Coharie Watershed, a 158 square mile area located in the coastal plain of eastern North Carolina. Statistical analysis indicated that research monitoring wells provided a greater probability of detecting pesticides in ground water than existing on-farm wells. Atrazine was the most frequently detected pesticide found in all wells, followed in order by fluometuron, carbofuran, metolachlor, alachlor, carbaryl, butylate, chlorothalonil, linuron and simazine. Ninety-seven percent of all wells had observed concentrations of nitrate-N, ranging from 0.1 to 30.1 mg/L. There was not a significant difference between research wells and existing wells for monitoring nitrate-N. Based on results of this study, existing drinking water wells can be used for monitoring nitrate; however, specialized stainless steel monitoring wells should be used for monitoring pesticides in ground water.

The molecular mechanisms by which mesenchymal cells differentiate into chondrocytes are still poorly understood. We have used the gene for a chondrocyte marker, the proalpha1(II) collagen gene (Col2a1), as a model to delineate a minimal sequence needed for chondrocyte expression and identify chondrocyte-specific proteins binding to this sequence. We previously localized a cartilage-specific enhancer to 156 bp of the mouse Col2a1 intron 1. We show here that four copies of a 48-bp subsegment strongly increased promoter activity in transiently transfected rat chondrosarcoma (RCS) cells and mouse primary chondrocytes but not in 10T1/2 fibroblasts. They also directed cartilage specificity in transgenic mouse embryos. These 48 bp include two 11-bp inverted repeats with only one mismatch. Tandem copies of an 18-bp element containing the 3' repeat strongly enhanced promoter activity in RCS cells and chondrocytes but not in fibroblasts. Transgenic mice harboring 12 copies of this 18-mer expressed luciferase in ribs and vertebrae and in isolated chondrocytes but not in noncartilaginous tissues except skin and brain. In gel retardation assays, an RCS cell-specific protein and another closely related protein expressed only in RCS cells and primary chondrocytes bound to a 10-bp sequence within the 18-mer. Mutations in these 10 bp abolished activity of the multimerized 18-bp enhancer, and deletion of these 10 bp abolished enhancer activity of 465- and 231-bp intron 1 segments. This sequence contains a low-affinity binding site for POU domain proteins, and competition experiments with a high-affinity POU domain binding site strongly suggested that the chondrocyte proteins belong to this family. Together, our results indicate that an 18-bp sequence in Col2a1 intron 1 controls chondrocyte expression and suggest that RCS cells and chondrocytes contain specific POU domain proteins involved in enhancer activity.

Based on our previous transgenic mice results, which strongly suggested that separate cell-specific cis-acting elements of the mouse pro-alpha 1(I) collagen promoter control the activity of the gene in different type I collagen-producing cells, we attempted to delineate a short segment in this promoter that could direct high-level expression selectively in osteoblasts. By generating transgenic mice harboring various fragments of the promoter, we identified a 117-bp segment (-1656 to -1540) that is a minimal sequence able to confer high-level expression of a lacZ reporter gene selectively in osteoblasts when cloned upstream of the proximal 220-bp pro-alpha 1(I) promoter. This 220-bp promoter by itself was inactive in transgenic mice and unable to direct osteoblast-specific expression. The 117-bp enhancer segment contained two sequences that appeared to have different functions. The A sequence (-1656 to -1628) was required to obtain expression of the lacZ gene in osteoblasts, whereas the C sequence (-1575 to -1540) was essential to obtain consistent and high-level expression of the lacZ gene in osteoblasts. Gel shift assays showed that the A sequence bound a nuclear protein present only in osteoblastic cells. A mutation in the A segment that abolished the binding of this osteoblast-specific protein also abolished lacZ expression in osteoblasts of transgenic mice.