Hypothermia or Machine Perfusion in Kidney Donors.

BACKGROUND: Therapeutic hypothermia in brain-dead organ donors has been shown to reduce delayed graft function in kidney recipients after transplantation. Data are needed on the effect of hypothermia as compared with machine perfusion on outcomes after kidney transplantation. METHODS: At six organ-procurement facilities in the United States, we randomly assigned brain-dead kidney donors to undergo therapeutic hypothermia (hypothermia group), ex situ kidney hypothermic machine perfusion (machine-perfusion group), or both (combination-therapy group). The primary outcome was delayed graft function in the kidney transplant recipients (defined as the initiation of dialysis during the first 7 days after transplantation). We also evaluated whether hypothermia alone was noninferior to machine perfusion alone and whether the combination of both methods was superior to each of the individual therapies. Secondary outcomes included graft survival at 1 year after transplantation. RESULTS: From 725 enrolled donors, 1349 kidneys were transplanted: 359 kidneys in the hypothermia group, 511 in the machine-perfusion group, and 479 in the combined-therapy group. Delayed graft function occurred in 109 patients (30%) in the hypothermia group, in 99 patients (19%) in the machine-perfusion group, and in 103 patients (22%) in the combination-therapy group. Adjusted risk ratios for delayed graft function were 1.72 (95% confidence interval [CI], 1.35 to 2.17) for hypothermia as compared with machine perfusion, 1.57 (95% CI, 1.26 to 1.96) for hypothermia as compared with combination therapy, and 1.09 (95% CI, 0.85 to 1.40) for combination therapy as compared with machine perfusion. At 1 year, the frequency of graft survival was similar in the three groups. A total of 10 adverse events were reported, including cardiovascular instability in 9 donors and organ loss in 1 donor owing to perfusion malfunction. CONCLUSIONS: Among brain-dead organ donors, therapeutic hypothermia was inferior to machine perfusion of the kidney in reducing delayed graft function after transplantation. The combination of hypothermia and machine perfusion did not provide additional protection. (Funded by Arnold Ventures; ClinicalTrials.gov number, NCT02525510.).

Differential effects of myosin activators on myocardial contractile function in non-failing and failing human hearts.

The second-generation myosin activator danicamtiv (DN) has shown improved function compared to the first generation myosin activator omecamtiv mecarbil (OM) in non-failing myocardium by enhancing cardiac force generation but attenuating slowed relaxation. However, whether the functional improvement with DN compared to OM persists in remodeled failing myocardium remain unknown. Therefore, this study aimed to investigate the differential contractile response to myosin activators in non-failing and failing myocardium. Mechanical measurements were performed in detergent-skinned myocardium isolated from donor and failing human hearts. Steady-state force, stretch activation responses, and loaded shortening velocity were analyzed at submaximal [Ca2+] in the absence or presence of 0.5 µmol/L OM or 2 µmol/L DN. The effects of DN and OM on Ca2+-sensitivity of force generation were determined by incubating myocardial preparations at various [Ca2+]. The inherent impairment in force generation and cross-bridge behavior sensitized failing myocardium to the effects of myosin activators. Specifically, increased Ca2+-sensitivity of force generation, slowed rates of cross-bridge recruitment and detachment following acute stretch, slowed loaded shortening velocity, and diminished power output were more prominent following treatment with OM or DN in failing myocardium compared to donor myocardium. Although these effects were less pronounced with DN compared to OM in failing myocardium, DN impaired contractile properties in failing myocardium that were not affected in donor myocardium. Our results indicate that similar to first-generation myosin activators, the DN-induced slowing of cross-bridge kinetics may result in a prolongation of systolic ejection and delayed diastolic relaxation in the heart failure setting.

Understanding the Final Disposition of Livers Declined After the Start of Procurement: A Nationwide Organ Procurement Organization Effort.

Declining a liver offer during organ procurement likely increases the risk of discard, but the specifics around late reallocation remain obscure. This voluntarily submitted, prospectively collected data describe late declines and the ultimate disposition of 893 livers. Once a liver suffered an intraoperative decline, only 49% of recovered livers were transplanted. Livers declined ≥80 minutes prior to cross-clamp were transplanted 80% of the time versus livers declined ≥80 minutes after cross-clamp, which were transplanted 45% of the time. The final disposition of these livers was into a predetermined backup patient (51%) or required an out-of-sequence expedited allocation (42%). Prerecovery imaging and prerecovery biopsy did not influence the ability to reallocate a liver, and livers from donors after circulatory death are rarely successfully reallocated. In conclusion, this study begins to shed light on this seemingly common practice. A total of 85% of centers had an intraoperative decline, but 4% of centers accounted for 25% of the declines. Organ procurement organizations often enter expedited liver allocation, and instituting a cross-clamp delay to allow for reallocation may influence the disposition of these liver grafts. Expedited allocation was more time consuming than allocation into a predetermined backup. Although a certain number of intraoperative declines probably suggests a healthy amount of donor selection aggressiveness at the time of the initial organ offer, the 47% risk of discard of livers declined intraoperatively suggests that United Network for Organ Sharing should consider systematically collecting data about intraoperative declines so we can learn more about this event that influences organ utilization.

Are parrots naive realists? Kea behave as if the real and virtual worlds are continuous.

Human psychology and animal cognition have increasingly used virtual stimuli to test cognitive abilities, with the expectation that participants are 'naive realists', that is, that they perceive virtual environments as both equivalent and continuous with real-life equivalents. However, there have been no attempts to investigate whether nonhuman subjects in fact behave as if physical processes in the virtual and real worlds are continuous. As kea parrots have previously shown the ability to transfer knowledge between real stimuli and both images on paper and images on touchscreens, here we test whether kea behave as naive realists and so expect physical processes to be continuous between the physical and virtual worlds. We find that, unlike infants, kea do not discriminate between these two contexts, and that they do not exhibit a preference for either. Our findings therefore validate the use of virtual stimuli as a powerful tool for testing the cognition of nonhuman animal species.

Outcomes, Satisfaction, and Costs of a Rheumatology Telemedicine Program: A Longitudinal Evaluation.

OBJECTIVES: Rural veterans with inflammatory arthritis (IA) lack medical access because of geographic barriers. Telemedicine (TM) holds great promise in relieving these disparities. We have prospectively measured patient-centered data surrounding a TM care program at a federal health system and compared these with usual care (UC). METHODS: Veterans with previously established IA were enrolled in TM follow-up. Data collected longitudinally before and after entering the program included Routine Assessment of Patient Index Data 3 (RAPID-3), out-of-pocket visit costs and distances traveled, and patient satisfaction instruments. Demographics were recorded. Similar data were collected on a convenience sample of concurrent IA patients receiving UC. RESULTS: Eighty-five patients were observed, including 25 receiving TM care and 60 receiving UC. No differences in demographics, satisfaction scores, or RAPID-3 were noted at baseline between groups. Univariate linear regression of cross-sectional baseline data suggests satisfaction instrument scores were predicted by RAPID-3 (ß = -0.64/10 points, p = 0.01), as well as distance (ß = -0.19/100 miles, p = 0.02) and cost (ß = -0.37/$100, p = 0.05). A multivariate model indicates both distance (ß = -0.17/100 miles, p = 0.02) and RAPID-3 (ß = -0.47/10 points, p < 0.03) were predictors for visit satisfaction. In longitudinal follow-up via TM, satisfaction (Δ = 0.03, p = 0.94) and RAPID-3 (Δ = 0.27, p = 0.89) remained similar to baseline among TM patients, whereas distance traveled (Δ = -384.8 miles/visit, p < 0.01) and visit costs (Δ = -$113.8/visit, p < 0.01) were reduced. CONCLUSIONS: Patient-reported outcomes for care delivered via TM were similar to UC, with significant cost and distance savings. Patient-centered factors such as distance to care should be considered in design care delivery models, as they appear to drive patient satisfaction in conjunction with disease control.

Human Schwann cells exhibit long-term cell survival, are not tumorigenic and promote repair when transplanted into the contused spinal cord.

The transplantation of rodent Schwann cells (SCs) provides anatomical and functional restitution in a variety of spinal cord injury (SCI) models, supporting the recent translation of SCs to phase 1 clinical trials for human SCI. Whereas human (Hu)SCs have been examined experimentally in a complete SCI transection paradigm, to date the reported behavior of SCs when transplanted after a clinically relevant contusive SCI has been restricted to the use of rodent SCs. Here, in a xenotransplant, contusive SCI paradigm, the survival, biodistribution, proliferation and tumorgenicity as well as host responses to HuSCs, cultured according to a protocol analogous to that developed for clinical application, were investigated. HuSCs persisted within the contused nude rat spinal cord through 6 months after transplantation (longest time examined), exhibited low cell proliferation, displayed no evidence of tumorigenicity and showed a restricted biodistribution to the lesion. Neuropathological examination of the CNS revealed no adverse effects of HuSCs. Animals exhibiting higher numbers of surviving HuSCs within the lesion showed greater volumes of preserved white matter and host rat SC and astrocyte ingress as well as axon ingrowth and myelination. These results demonstrate the safety of HuSCs when employed in a clinically relevant experimental SCI paradigm. Further, signs of a potentially positive influence of HuSC transplants on host tissue pathology were observed. These findings show that HuSCs exhibit a favorable toxicity profile for up to 6 months after transplantation into the contused rat spinal cord, an important outcome for FDA consideration of their use in human clinical trials.

How do soundboard-trained dogs respond to human button presses? An investigation into word comprehension.

Past research on interspecies communication has shown that animals can be trained to use Augmentative Interspecies Communication (AIC) devices, such as soundboards, to make simple requests of their caretakers. The recent uptake in AIC devices by hundreds of pet owners around the world offers a novel opportunity to investigate whether AIC is possible with owner-trained family dogs. To answer this question, we carried out two studies to test pet dogs' ability to recognise and respond appropriately to food-related, play-related, and outside-related words on their soundboards. One study was conducted by researchers, and the other by citizen scientists who followed the same procedure. Further, we investigated whether these behaviours depended on the identity of the person presenting the word (unfamiliar person or dog's owner) and the mode of its presentation (spoken or produced by a pressed button). We find that dogs produced contextually appropriate behaviours for both play-related and outside-related words regardless of the identity of the person producing them and the mode in which they were produced. Therefore, pet dogs can be successfully taught by their owners to associate words recorded onto soundboard buttons to their outcomes in the real world, and they respond appropriately to these words even when they are presented in the absence of any other cues, such as the owner's body language.

Scalable culture techniques to generate large numbers of purified human Schwann cells for clinical trials in human spinal cord and peripheral nerve injuries.

OBJECTIVE: Schwann cells (SCs) have been shown to play an essential role in axon regeneration in both peripheral nerve injuries (PNIs) and spinal cord injuries (SCIs). The transplantation of SCs as an adjunctive therapy is currently under investigation in human clinical trials due to their regenerative capacity. Therefore, a reliable method for procuring large quantities of SCs from peripheral nerves is necessary. This paper presents a well-developed, validated, and optimized manufacturing protocol for clinical-grade SCs that are compliant with Current Good Manufacturing Practices (CGMPs). METHODS: The authors evaluated the SC culture manufacturing data from 18 clinical trial participants who were recruited for autologous SC transplantation due to subacute SCI (n = 7), chronic SCI (n = 8), or PNIs (n = 3). To initiate autologous SC cultures, a mean nerve length of 11.8 ± 3.7 cm was harvested either from the sural nerve alone (n = 17) or with the sciatic nerve (n = 1). The nerves were digested with enzymes and SCs were isolated and further expanded in multiple passages to meet the dose requirements for transplantation. RESULTS: An average yield of 87.2 ± 89.2 million cells at P2 and 150.9 ± 129.9 million cells at P3 with high viability and purity was produced. Cell counts and rates of expansion increased with each subsequent passage from P0 to P3, with the largest rate of expansion between P2 and P3. Larger harvest nerve lengths correlated significantly with greater yields at P0 and P1 (p < 0.05). In addition, a viability and purity above 90% was sustained throughout all passages in nearly all cell products. CONCLUSIONS: This study presents reliable CGMP-compliant manufacturing methods for autologous SC products that are suitable for regenerative treatment of patients with SCI, PNI, or other conditions.

Schwann cell dedifferentiation is independent of mitogenic signaling and uncoupled to proliferation: role of cAMP and JNK in the maintenance of the differentiated state.

Myelinating Schwann cells (SCs) are highly plastic cells that are able to dedifferentiate and re-enter the cell cycle. However, the molecular signals controlling dedifferentiation are not completely understood. Because a connection between mitogenic signaling and myelin loss has been suggested, we investigated the role of cAMP, a strong inducer of the myelinating phenotype, and mitogenic factors activating receptor tyrosine kinases (RTKs) on SC dedifferentiation. We herein provide evidence indicating that cAMP was required to not only initiate but also maintain a state of differentiation because SCs rapidly dedifferentiated and became competent to resume proliferation upon the removal of cAMP stimulation. Surprisingly, isolated SCs could undergo multiple cycles of differentiation and dedifferentiation upon cAMP addition and removal, respectively, in the absence of mitogenic factors and without entering the cell cycle. Conversely, the activation of RTKs and the ERK cascade by a variety of growth factors, including neuregulin, was not sufficient to initiate dedifferentiation in the presence of cAMP. Importantly, a reduction of cAMP triggered dedifferentiation through a mechanism that required JNK, rather than ERK, activity and an induction of the expression of c-Jun, a transcriptional inhibitor of myelination. In summary, the reversible transition from an undifferentiated to a myelinating state was dependent on cAMP but independent of RTK signaling and cell cycle progression, further indicating that dedifferentiation and proliferation are uncoupled and differentially regulated events in SCs.

Kea (Nestor notabilis) fail a loose-string connectivity task.

Naïve individuals of some bird species can rapidly solve vertical string-pulling tasks with virtually no errors. This has led to various hypotheses being proposed which suggest that birds mentally simulate the effects of their actions on strings. A competing embodied cognition hypothesis proposes that this behaviour is instead modulated by perceptual-motor feedback loops, where feedback of the reward moving closer acts as an internal motivator for functional behaviours, such as pull-stepping. To date, the kea parrot has produced some of the best performances of any bird species at string-pulling tasks. Here, we tested the predictions of the four leading hypotheses for the cognition underpinning bird string-pulling by presenting kea with a horizontal connectivity task where only one of two loose strings was connected to the reward, both before and after receiving perceptual-motor feedback experience. We find that kea fail the connectivity task both before and after perceptual-motor feedback experience, suggesting not only that kea do not mentally simulate their string-pulling actions, but also that perceptual-motor feedback alone is insufficient in eliciting successful performance in the horizontal connectivity task. This suggests a more complex interplay of cognitive factors underlies this iconic example of animal problem-solving.

Self-care tooling innovation in a disabled kea (Nestor notabilis).

Tooling is associated with complex cognitive abilities, occurring most regularly in large-brained mammals and birds. Among birds, self-care tooling is seemingly rare in the wild, despite several anecdotal reports of this behaviour in captive parrots. Here, we show that Bruce, a disabled parrot lacking his top mandible, deliberately uses pebbles to preen himself. Evidence for this behaviour comes from five lines of evidence: (i) in over 90% of instances where Bruce picked up a pebble, he then used it to preen; (ii) in 95% of instances where Bruce dropped a pebble, he retrieved this pebble, or replaced it, in order to resume preening; (iii) Bruce selected pebbles of a specific size for preening rather than randomly sampling available pebbles in his environment; (iv) no other kea in his environment used pebbles for preening; and (v) when other individuals did interact with stones, they used stones of different sizes to those Bruce preened with. Our study provides novel and empirical evidence for deliberate self-care tooling in a bird species where tooling is not a species-specific behaviour. It also supports claims that tooling can be innovated based on ecological necessity by species with sufficiently domain-general cognition.

Non-Modifiable Risk Factors for Stress Fractures in Military Personnel Undergoing Training: A Systematic Review.

A fracture, being an acquired rupture or break of the bone, is a significant and debilitating injury commonly seen among athletes and military personnel. Stress fractures, which have a repetitive stress aetiology, are highly prevalent among military populations, especially those undergoing training. The primary aim of this review is to identify non-modifiable risk factors for stress fractures in military personnel undergoing training. A systematic search was conducted of three major databases to identify studies that explored risk factors for stress fractures in military trainees. Critical appraisal, data extraction, and a narrative synthesis were conducted. Sixteen articles met the eligibility criteria for the study. Key non-modifiable risk factors identified were prior stress fracture and menstrual dysfunction, while advancing age and race other than black race may be a risk factor. To reduce the incidence of stress fractures in military trainees, mitigating modifiable risk factors among individuals with non-modifiable risk factors (e.g., optimising conditioning for older trainees) or better accommodating non-modifiable factors (for example, extending training periods and reducing intensity to facilitate recovery and adaptation) are suggested, with focus on groups at increased risk identified in this review.

Variations in brain gray matter associated with chronic pain.

Variations in brain gray matter volume and density have been reported in association with a variety of disorders characterized by chronic pain, including chronic low back pain, fibromyalgia, and irritable bowel syndrome. Correlation analyses have demonstrated relationships between morphometric and clinical variables. However, conclusions regarding the nature of these relationships are problematic given that currently available data are derived exclusively from cross-sectional studies. Further efforts to determine the relationship between chronic pain and variations in brain morphometry will depend in part on longitudinal studies of patients at various stages of illness, as well as those at risk of the development of chronic pain. Interpretation of findings from morphometric studies also must take into account genetic and experiential factors that recently have been demonstrated to influence brain morphometry and the risk of developing chronic pain.

Universal Health Literacy Precautions Are Associated With a Significant Increase in Medication Adherence in Vulnerable Rheumatology Patients.

OBJECTIVE: Our objective was to determine the impact of the Health Literacy Universal Precautions Toolkit, adapted for rheumatology, on medication adherence, patient satisfaction, and feasibility in all patients; its effect on the clinical disease activity index (CDAI) was studied in a rheumatoid arthritis (RA) subpopulation. METHODS: Data collected during a 6-month prospective quality assurance intervention was compared with data from a prior 6-month period. Interventions included 1) encouraging questions, 2) teach-back communication, and 3) brown-bag medication review. Analysis was performed using linear regression or generalized estimating equation (GEE) regression. RESULTS: During the intervention period, 46 physicians completed 1737 patient visits. Questions were encouraged, and teach-back communication was performed in more than 90% of visits. Brown-bag medication reviews were performed in 47% of visits overall and 69% of visits in a subgroup that received additional reminder calls. Visit duration and patient satisfaction were not significantly increased. Adherence for rheumatology-related medications that were prescribed both before and during the intervention increased by 22% (P ≤ 0.001; by GEE). Teach-back communication predicted a statistically significant improvement in medication adherence in this subpopulation (by linear regression). The mean CDAI did not improve; however, African American race and Hispanic ethnicity were associated with a decreased CDAI (by GEE). CONCLUSION: Implementation of the Health Literacy Universal Precautions Toolkit, adapted for rheumatology, improved medication adherence in our safety-net clinic, with particularly strong effects seen with teach-back communication. In certain populations, use of the toolkit may also improve RA disease activity. This is the first study to document improved medication adherence with this intervention in a real-world setting.

Rheumatology Clinicians' Perceptions of Telerheumatology Within the Veterans Health Administration: A National Survey Study.

INTRODUCTION: The Department of Veterans Affairs Veterans Health Administration (VA) Strategic Plan (Fiscal Year 2018-2024) identified four priorities for care including easy access, timely and integrated care, accountability, and modernization, all of which can be directly or indirectly impacted by telemedicine technologies. These strategic goals, coupled with an anticipated rheumatology workforce shortage, has created a need for additional care delivery methods such as clinical video telehealth application to rheumatology (ie, telerheumatology). Rheumatology clinician perceptions of clinical usefulness telerheumatology have received limited attention in the past. The present study aimed to evaluate rheumatologists' perceptions of and experiences with telemedicine, generally, and telerheumatology, specifically, within the VA. MATERIALS AND METHODS: A 38-item survey based on an existing telehealth providers' satisfaction survey was developed by two VA rheumatologists with experience in telemedicine as well as a social scientist experienced in survey development and user experience through an iterative process. Questions probed VA rheumatology clinician satisfaction with training and information technology (IT) supports, as well as barriers to using telemedicine. Additionally, clinician perceptions of the impact and usefulness of and appropriate clinical contexts for telerheumatology were evaluated. The survey was disseminated online via VA REDCap to members of the VA Rheumatology Consortium (VARC) through a LISTSERV. The study protocol was approved by the host institution IRB through expedited review. Survey responses were analyzed using descriptive statistics. RESULTS: Forty-five anonymous responses (20% response rate) were collected. Of those who responded, 47% were female, 98% were between 35 and 64 years old, 71% reported working at an academic center, and the majority was physician-level practitioners (98%). Respondents generally considered themselves to be tech savvy (58%). Thirty-six percent of the sample reported past experience with telemedicine, and, of those, 29% reported experience with telerheumatology specifically. Clinicians identified the greatest barrier to effective telerheumatology as the inability to perform a physical exam (71%) but agreed that telerheumatology is vital to increasing access to care (59%) and quality of care (40%) in the VA. Overall, regardless of experience with telemedicine, respondents reported that telerheumatology was more helpful for management of rheumatologic conditions rather than initial diagnosis. CONCLUSIONS: While the majority of rheumatology clinicians did not report past experience with telerheumatology, they agreed that it has potential to further the VA mission of improved access and quality of care. Rheumatology clinicians felt the suitability of telerheumatology is dependent on the phase of care. As remote care technologies continue to be rapidly adopted into clinic, clinician perceptions of and experiences with telemedicine will need to be addressed in order to maintain high-quality and clinician- and patient-centric care within VA rheumatology.

Neurotrophic factors improve motoneuron survival and function of muscle reinnervated by embryonic neurons.

Motoneuron death can occur over several spinal levels with disease or trauma, resulting in muscle denervation. We tested whether cotransplantation of embryonic neurons with 1 or more neurotrophic factors into peripheral nerve improved axon regeneration, muscle fiber area, reinnervation, and function to a greater degree than cell transplantation alone. Sciatic nerves of adult Fischer rats were cut to denervate muscles; 1 week later, embryonic ventral spinal cord cells (days 14-15) were transplanted into the tibial nerve stump as the only source of neurons for muscle reinnervation. Factors that promote motoneuron survival (cardiotrophin 1; fibroblast growth factor 2; glial cell line-derived neurotrophic factor; insulin-like growth factor 1; leukemia inhibitory factor; and hepatocyte growth factor) were added to the transplant individually or in combinations. Inclusion of a single factor with the cells resulted in comparable myelinated axon counts, muscle fiber areas, and evoked electromyographic activity to cells alone 10 weeks after transplantation. Only cell transplantation with glial cell line-derived neurotrophic factor, hepatocyte growth factor, and insulin-like growth factor 1 significantly increased motoneuron survival, myelinated axon counts, muscle reinnervation, and evoked electromyographic activity compared with cells alone. Thus, immediate application of a specific combination of factors to dissociated embryonic neurons improves survival of motoneurons and the long-term function of reinnervated muscle.

GDNF-enhanced axonal regeneration and myelination following spinal cord injury is mediated by primary effects on neurons.

We previously demonstrated that coadministration of glial cell line-derived neurotrophic factor (GDNF) with grafts of Schwann cells (SCs) enhanced axonal regeneration and remyelination following spinal cord injury (SCI). However, the cellular target through which GDNF mediates such actions was unclear. Here, we report that GDNF enhanced both the number and caliber of regenerated axons in vivo and increased neurite outgrowth of dorsal root ganglion neurons (DRGN) in vitro, suggesting that GDNF has a direct effect on neurons. In SC-DRGN coculture, GDNF significantly increased the number of myelin sheaths produced by SCs. GDNF treatment had no effect on the proliferation of isolated SCs but enhanced the proliferation of SCs already in contact with axons. GDNF increased the expression of the 140 kDa neural cell adhesion molecule (NCAM) in isolated SCs but not their expression of the adhesion molecule L1 or the secretion of the neurotrophins NGF, NT3, or BDNF. Overall, these results support the hypothesis that GDNF-enhanced axonal regeneration and SC myelination is mediated mainly through a direct effect of GDNF on neurons. They also suggest that the combination of GDNF administration and SC transplantation may represent an effective strategy to promote axonal regeneration and myelin formation after injury in the spinal cord.

Non-antagonistic relationship between mitogenic factors and cAMP in adult Schwann cell re-differentiation.

The expression of myelination-associated genes (MGs) can be induced by cyclic adenosine monophosphate (cAMP) elevation in isolated Schwann cells (SCs). To further understand the effect of known SC mitogens in the regulation of SC differentiation, we studied the response of SCs isolated from adult nerves to combined cAMP, growth factors, including neuregulin, and serum. In adult SCs, the induction of MGs by cAMP coincided with the loss of genes expressed in non-myelin-forming SCs and with a change in cell morphology from a bipolar to an expanded epithelial-like shape. Prolonged treatment with high doses of cAMP-stimulating agents, as well as low cell density, was required for the induction of SC differentiation. Stimulation with serum, neuregulin alone, or other growth factors including PDGF, IGF and FGF, increased SC proliferation but did not induce the expression of MGs or the associated morphological change. Most importantly, when these factors were administered in combination with cAMP-stimulating agents, SC proliferation was synergistically increased without reducing the differentiating activity of cAMP. Even though the initiation of DNA synthesis and the induction of differentiation were mostly incompatible events in individual cells, SCs were able to differentiate under conditions that also supported active proliferation. Overall, the results indicate that in the absence of neurons, cAMP can trigger SC re-differentiation concurrently with, but independently of, growth factor signaling.

Enhanced pain perception in rheumatoid arthritis: novel considerations.

Enhanced pain perception is common among patients with rheumatoid arthritis (RA). Given the putative role of proinflammatory cytokines in the development of hyperalgesia, a greater understanding of factors that facilitate increased cytokine expression in RA stands to increase understanding of the sources of enhanced pain perception. Patients with RA have significantly greater stress-induced proinflammatory cytokine release. Although absolute deficiencies in cortisol have not been demonstrated, functional abnormalities have been described, including "abnormally normal" cortisol levels in the face of increased inflammation and deficient responses to stressful challenges. Parasympathetic insufficiency has also been demonstrated, which may enhance pain perception indirectly through disinhibited cytokine expression. Several psychological variables have also been demonstrated to affect pain perception in patients with RA. Identification of factors that contribute to enhanced pain perception in RA may aid in the development of novel analgesic strategies that, in turn, may decrease disease activity and improve general clinical outcomes.

Symptom clusters in fibromyalgia: potential utility in patient assessment and treatment evaluation.

BACKGROUND: Recent evidence points to the likelihood of heterogeneity in the presentation and, perhaps, etiology of fibromyalgia (FM). A clearer understanding of the symptomatology and consideration of potential FM subtypes could add insights regarding this condition. OBJECTIVE: The aim of this study was to determine whether clusters could be identified among 20 symptoms that participants in a prior online study identified and to elucidate the underlying structure of resultant clusters. METHODS: Factor analysis was used on data from a study sponsored by the National Fibromyalgia Association in which 2,569 persons with FM responded to an online survey during a 3-day period in 2005. RESULTS: In this well-educated, primarily Caucasian sample, morning stiffness, fatigue, and not feeling rested in the morning were the symptoms with the highest severity scores. A series of exploratory factor analyses and subsequent confirmatory factor analysis with Cronbach's alpha testing led to a five-factor model with the following domains containing 17 symptoms: Somatic, Distress, Fibromyalgia Core, Dyscognition, and Sleep Problems. DISCUSSION: The findings support the heterogeneity of the FM experience and the presence of symptom clusters within the greater spectrum of symptoms comprising the FM syndrome. These observations suggest the possibility of tailoring interventions based upon individual patient symptomatology. Further work is needed to develop symptom inventories that can be used in clinical trials as outcome metrics and by healthcare providers to describe clinical burden and effect of treatments.