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.).

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.

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.

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.

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.

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.

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.

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.

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.

Limited Health Literacy and Patient Confusion About Rheumatoid Arthritis Patient Global Assessments and Model Disease States.

OBJECTIVE: Patient global assessment visual analog scales (PGA-VAS) are widely used in rheumatoid arthritis (RA) practice and research, and low PGA-VAS scores are required for remission. Vulnerable patients with RA may have difficulty completing the PGA-VAS. There is limited information about both patients' perceptions of PGA-VAS and how patients score VAS model disease states. The objective of this study was to understand the perspectives of vulnerable patients regarding PGA-VAS and model disease states. METHODS: We enrolled patients with RA at Denver Health (n = 300). Subjects completed the PGA-VAS in the Disease Activity Score in 28 joints and the Multidimensional Health Assessment Questionnaire and completed a questionnaire regarding these PGA-VAS. Subjects also scored remission, mild, moderate, and severe model disease states by VAS. We performed analyses by linear and logistic regression and by using summary statistics. Outcomes included whether subjects found the PGA-VAS confusing, whether subjects' responses to the model disease states followed a natural progression (remission

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.

Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis.

AIM: To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS: Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs (DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics. RESULTS: Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events (-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events (+5.85 mg/dL, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events (-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (ß = -0.58, P = 0.01) and hydroxychloroquine (ß = -5.78, P = 0.01) use as predictors of lower post-medication-initiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure (ß = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events. CONCLUSION: No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.

Drug-Induced Gastrointestinal and Hepatic Disease Associated with Biologics and Nonbiologic Disease-Modifying Antirheumatic Drugs.

A variety of gastrointestinal adverse drug reactions are seen in nearly all conventional antirheumatic medications, ranging from nausea to life-threatening drug-induced liver injury. Rheumatologists should be particularly familiar with hepatotoxicity associated with long-term methotrexate use, and the range of unique hepatic, biliary, and pancreatic manifestations associated with azathioprine. Hepatitis B virus reactivation is the most serious gastrointestinal disease risk associated with many biological therapies, particularly rituximab. Gastrointestinal perforation may be a specific concern for agents directed at interleukin-6 pathways, and some reports have raised the question of whether interleukin-17 inhibition may elevate inflammatory bowel disease risk.

Long-Term Denervated Rat Schwann Cells Retain Their Capacity to Proliferate and to Myelinate Axons in vitro.

Functional recovery is poor after peripheral nerve injury and delayed surgical repair or when nerves must regenerate over long distances to reinnervate distant targets. A reduced capacity of Schwann cells (SCs) in chronically denervated distal nerve stumps to support and interact with regenerating axons may account for the poor outcome. In an in vitro system, we examined the capacity of adult, long-term denervated rat SCs to proliferate and to myelinate neurites in co-cultures with fetal dorsal root ganglion (DRG) neurons. Non-neuronal cells were counted immediately after their isolation from the distal sciatic nerve stumps that were subjected to acute denervation of 7 days or chronic denervation of either 7 weeks or 17 months. Thereafter, equal numbers of the non-neural cells were co-cultured with purified dissociated DRG neurons for 5 days. The co-cultures were then treated with 3H-Thymidine for 24 h to quantitate SC proliferation with S100 immunostaining and autoradiography. After a 24-day period of co-culture, Sudan Black staining was used to visualize and count myelin segments that were elaborated around DRG neurites by the SCs. Isolated non-neural cells from 7-week chronically denervated nerve stumps increased 2.5-fold in number compared to ~2 million in 7 day acutely denervated stumps. There were only <0.2 million cells in the 17-week chronically denervated stumps. Nonetheless, these chronically denervated SCs maintained their proliferative capacity although the capacity was reduced to 30% in the 17-month chronically denervated distal nerve stumps. Moreover, the chronically denervated SCs retained their capacity to myelinate DRG neurites: there was extensive myelination of the neurites by the acutely and chronically denervated SCs after 24 days co-culture. There were no significant differences in the extent of myelination. We conclude that the low numbers of surviving SCs in chronically denervated distal nerve stumps retain their ability to respond to axonal signals to divide and to elaborate myelin. However, their low numbers consequent to their poor survival and their reduced capacity to proliferate account, at least in part, for the poor functional recovery after delayed surgical repair of injured nerve and/or the repair of injured nerves far from their target organs.

From transplanting Schwann cells in experimental rat spinal cord injury to their transplantation into human injured spinal cord in clinical trials.

Among the potential therapies designed to repair the injured spinal cord is cell transplantation, notably the use of autologous adult human Schwann cells (SCs). Here, we detail some of the critical research accomplished over the last four decades to establish a foundation that enables these cells to be tested in clinical trials. New culture systems allowed novel information to be gained about SCs, including discovering ways to stimulate their proliferation to acquire adequately large numbers for transplantation into the injured human spinal cord. Transplantation of rat SCs into rat models of spinal cord injury has demonstrated that SCs promote repair of injured spinal cord. Additional work required to gain approval from the Food and Drug Administration for the first SC trial in the Miami Project is disclosed. This trial and a second one now underway are described.

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.

Safety of Autologous Human Schwann Cell Transplantation in Subacute Thoracic Spinal Cord Injury.

The rationale for implantation of autologous human Schwann cells (SCs) in persons with subacute spinal cord injury (SCI) is based on evidence that transplanted SCs are neuroprotective, support local axonal plasticity, and are capable of myelinating axons. A Phase I clinical trial was conducted to evaluate the safety of autologous human SC transplantation into the injury epicenter of six subjects with subacute SCI. The trial was an open-label, unblinded, non-randomized, non-placebo controlled study with a dose escalation design and standard medical rehabilitation. Participants were paraplegics with neurologically complete, trauma-induced spinal lesions. Autologous SCs were cultured in vitro from a sural nerve harvested from each participant and injected into the epicenter of the spinal lesion. Outcome measures for safety were protocol compliance, feasibility, adverse events, stability of neurological level, absence of detectable mass lesion, and the emergence of clinically significant neuropathic pain or muscle spasticity no greater than expected for a natural course cohort. One year post-transplantation, there were no surgical, medical, or neurological complications to indicate that the timing or procedure for the cell transplantation was unsafe. There were no adverse events or serious adverse events related to the cell therapy. There was no evidence of additional spinal cord damage, mass lesion, or syrinx formation. We conclude that it is feasible to identify eligible candidates, appropriately obtain informed consent, perform a peripheral nerve harvest to obtain SCs within 5-30 days of injury, and perform an intra-spinal transplantation of highly purified autologous SCs within 4-7 weeks of injury.

Non-surgical factors influencing lymph node yield in colon cancer.

There are numerous factors which can affect the lymph node (LN) yield in colon cancer specimens. The aim of this paper was to identify both modifiable and non-modifiable factors that have been demonstrated to affect colonic resection specimen LN yield and to summarise the pertinent literature on these topics. A literature review of PubMed was performed to identify the potential factors which may influence the LN yield in colon cancer resection specimens. The terms used for the search were: LN, lymphadenectomy, LN yield, LN harvest, LN number, colon cancer and colorectal cancer. Both non-modifiable and modifiable factors were identified. The review identified fifteen non-surgical factors: (13 non-modifiable, 2 modifiable) which may influence LN yield. LN yield is frequently reduced in older, obese patients and those with male sex and increased in patients with right sided, large, and poorly differentiated tumours. Patient ethnicity and lower socioeconomic class may negatively influence LN yield. Pre-operative tumour tattooing appears to increase LN yield. There are many factors that potentially influence the LN yield, although the strength of the association between the two varies greatly. Perfecting oncological resection and pathological analysis remain the cornerstones to achieving good quality and quantity LN yields in patients with colon cancer.

Acute stimulation of transplanted neurons improves motoneuron survival, axon growth, and muscle reinnervation.

Few options exist for treatment of pervasive motoneuron death after spinal cord injury or in neurodegenerative diseases such as amyotrophic lateral sclerosis. Local transplantation of embryonic motoneurons into an axotomized peripheral nerve is a promising approach to arrest the atrophy of denervated muscles; however, muscle reinnervation is limited by poor motoneuron survival. The aim of the present study was to test whether acute electrical stimulation of transplanted embryonic neurons promotes motoneuron survival, axon growth, and muscle reinnervation. The sciatic nerve of adult Fischer rats was transected to mimic the widespread denervation seen after disease or injury. Acutely dissociated rat embryonic ventral spinal cord cells were transplanted into the distal tibial nerve stump as a neuron source for muscle reinnervation. Immediately post-transplantation, the cells were stimulated at 20 Hz for 1 h. Other groups were used to control for the cell transplantation and stimulation. When neurons were stimulated acutely, there were significantly more neurons, including cholinergic neurons, 10 weeks after transplantation. This led to enhanced numbers of myelinated axons, reinnervation of more muscle fibers, and more medial and lateral gastrocnemius muscles were functionally connected to the transplant. Reinnervation reduced muscle atrophy significantly. These data support the concept that electrical stimulation rescues transplanted motoneurons and facilitates muscle reinnervation.

Realizing the maximum potential of Schwann cells to promote recovery from spinal cord injury.

Transplantation of Schwann cells (SCs) has been extensively investigated as a therapeutic intervention in rodent models of spinal cord injury (SCI). Here we review both strengths and weaknesses of this approach and discuss additional strategies for maximizing the potential of SCs to repair the injured spinal cord. With no additional treatments, SCs were consistently shown to provide a bridge across the lesion site, supporting the ingrowth of sensory and propriospinal axons, to myelinate axons and to decrease the size of cavities formed after injury. Supraspinal axons did not, however, grow onto the bridge, axons failed to traverse the caudal SC-host cord interface and transplanted SC survival was poor. More recent studies have shown that the potential of SC transplantation as a therapeutic approach can be strongly enhanced by combining additional strategies . For example, combining SC transplantation with elevation of cAMP levels resulted in growth of brainstem axons into the SC graft and caudal to the lesion and in significant improvements in locomotion. Axon growth (and functional improvement) have been increased by strategies to raise neurotrophin levels, either by injection or by genetic modification of the SCs before transplantation. A major problem in maximizing SC potential in injured cord has been in achieving good integration of the transplanted cells with the adjacent cord parenchyma. Several previous studies suggested an ability of SCs to migrate extensively in CNS tissue when astroctyes were absent and to myelinate CNS axons. Furthermore, in some cases involving very limited injury, SCs migrated and integrated well even in the presence of host astrocytes. Consistent with these observations, treatments with an enzyme, chondroitinase, to modify the SC-astrocyte interface surrounding the graft, have shown much promise. Very new studies have shown that SCs derived from SC precursors show a higher ability to survive, integrate well with host tissue and support brainstem axon growth into and beyond the graft, confirming the innate promise of SCs in spinal cord repair. We review one clinical trial already underway in Iran testing SC transplantation in patients with SCI. Finally, we briefly describe a protocol, adaptable to the principles of good manufacturing practice, for generating large numbers of human SCs. Overall, the available evidence suggests that SCs, especially when used in combination with other treatments, offer one of the best hopes we have today of devising an effective treatment for spinal cord repair.