Degeneration of the Injured Cervical Cord Is Associated with Remote Changes in Corticospinal Tract Integrity and Upper Limb Impairment

Background

Traumatic spinal cord injury (SCI) leads to disruption of axons and macroscopic tissue loss. Using diffusion tensor imaging (DTI), we assessed degeneration of the corticospinal tract (CST) in the cervical cord above a traumatic lesion and explored its relationship with cervical atrophy, remote axonal changes within the cranial CST and upper limb function.

Methods

Nine cervical injured volunteers with bilateral motor and sensory impairment and ten controls were studied. DTI of the cervical cord and brain provided measurements of fractional anisotropy (FA), while anatomical MRI assessed cross-sectional spinal cord area (i.e. cord atrophy). Spinal and central regions of interest (ROI) included the bilateral CST in the cervical cord and brain. Regression analysis identified correlations between spinal FA and cranial FA in the CST and disability.

Results

In individuals with SCI, FA was significantly lower in both CSTs throughout the cervical cord and brain when compared with controls (p≤0.05). Reduced FA of the cervical cord in patients with SCI was associated with smaller cord area (p = 0.002) and a lower FA of the cranial CST at the internal capsule level (p = 0.001). Lower FA in the cervical CST also correlated with impaired upper limb function, independent of cord area (p = 0.03).

Conclusion

Axonal degeneration of the CST in the atrophic cervical cord, proximal to the site of injury, parallels cranial CST degeneration and is associated with disability. This DTI protocol can be used in longitudinal assessment of microstructural changes immediately following injury and may be utilised to predict progression and monitor interventions aimed at promoting spinal cord repair.     

Cobalamin Analogues in Humans: A Study on Maternal and Cord Blood

Background

Haptocorrin (HC) carries cobalamin analogues (CorA), but whether CorA are produced in the body is unknown. All cobalamins (Cbl) to the foetus are delivered by the Cbl-specific protein transcobalamin (TC), and therefore analysis of cord serum for CorA may help to clarify the origin of CorA.

Methods

HC-CorA were quantified in paired samples of cord serum from newborns and serum from mothers (n = 69).

Results

The CorA-concentration was higher in cord serum (median = 380, range: 41–780 pmol/L) than in serum from the mothers (median = 160, range: 64–330 pmol/L), (p<0.0001). HPLC-analysis showed CorA-peaks with retention times of 13.5, 14,5 and 16.5 min in samples from both the mother and cord serum. The peak with retention time 16.5 min constituted 24% (mother) and 45% (cord serum) of the total amount CorA, and eluted as does dicyanocobinamide.

Conclusion

Our results support that CorA in the human body are derived from Cbl.     

A Meta-Analysis of the Motion Function through the Therapy of Spinal Cord Injury with Intravenous Transplantation of Bone Marrow Mesenchymal Stem Cells in Rats

Background

To compare the efficacy of the therapy of spinal cord injury with intravenous transplantation of bone marrow mesenchymal stem cells (BMSCs) by Meta-analysis.

Methods

Studies of the BBB scores after intravenous transplantation of BMSCs were searched out from Pubmed, SCI, Cochrane Library, Chinese journal full-text database, China Biology Medicinedisc and Wanfang data-base and analyzed by Review Manager 5.2.5.

Results

Nine randomized controlled animal trials were selected with 235 rats enrolled. The studies are divided to different subgroups by different models of SCI and different time to transplantion. The results of Meta-analysis in different subgroups both indicated that the rats of experimental group (BMSCs group) got better BBB scores than control group at 1, 3 and over 5 weeks after intravenous transplantation of BMSCs with significant differences. The heterogeneity between impacted injury model and oppressed injury model subgroups decreased with the passage of time (I² = 75.8%, 39.7%, 0%). No heterogeneity was found between 3 d and 7 d subgroups.

Conclusion

The intravenous transplantation of BMSCs is an efficient way to cure spinal cord injury, which can improve the motor function of rats. The therapeutic window is wide.     

Analysis of Host-Mediated Repair Mechanisms after Human CNS-Stem Cell Transplantation for Spinal Cord Injury: Correlation of Engraftment with Recovery

Background

Human central nervous system-stem cells grown as neurospheres (hCNS-SCns) self-renew, are multipotent, and have potential therapeutic applications following trauma to the spinal cord. We have previously shown locomotor recovery in immunodeficient mice that received a moderate contusion spinal cord injury (SCI) and hCNS-SCns transplantation 9 days post-injury (dpi). Engrafted hCNS-SCns exhibited terminal differentiation to myelinating oligodendrocytes and synapse-forming neurons. Further, selective ablation of human cells using Diphtheria toxin (DT) abolished locomotor recovery in this paradigm, suggesting integration of human cells within the mouse host as a possible mechanism for the locomotor improvement. However, the hypothesis that hCNS-SCns could alter the host microenvironment as an additional or alternative mechanism of recovery remained unexplored; we tested that hypothesis in the present study.

Methods and Findings

Stereological quantification of human cells using a human-specific cytoplasmic marker demonstrated successful cell engraftment, survival, migration and limited proliferation in all hCNS-SCns transplanted animals. DT administration at 16 weeks post-transplant ablated 80.5% of hCNS-SCns. Stereological quantification for lesion volume, tissue sparing, descending serotonergic host fiber sprouting, chondroitin sulfate proteoglycan deposition, glial scarring, and angiogenesis demonstrated no evidence of host modification within the mouse spinal cord as a result of hCNS-SCns transplantation. Biochemical analyses supplemented stereological data supporting the absence of neural stem-cell mediated host repair. However, linear regression analysis of the number of engrafted hCNS-SCns vs. the number of errors on a horizontal ladder beam task revealed a strong correlation between these variables (r = −0.78, p<0.05), suggesting that survival and engraftment were directly related to a quantitative measure of recovery.

Conclusions

Altogether, the data suggest that the locomotor improvements associated with hCNS-SCns transplantation were not due to modifications within the host microenvironment, supporting the hypothesis that human cell integration within the host circuitry mediates functional recovery following a 9 day delayed transplant.     

Cranialization of the Frontal Sinus for Secondary Mucocele Prevention following Open Surgery for Benign Frontal Lesions

Objective

To compare frontal sinus cranialization to obliteration for future prevention of secondary mucocele formation following open surgery for benign lesions of the frontal sinus.

Study Design

Retrospective case series.

Setting

Tertiary academic medical center.

Patients

Sixty-nine patients operated for benign frontal sinus pathology between 1994 and 2011.

Interventions

Open excision of benign frontal sinus pathology followed by either frontal obliteration (n = 41, 59%) or frontal cranialization (n = 28, 41%).

Main Outcome Measures

The prevalence of post-surgical complications and secondary mucocele formation were compiled.

Results

Pathologies included osteoma (n = 34, 49%), mucocele (n = 27, 39%), fibrous dysplasia (n = 6, 9%), and encephalocele (n = 2, 3%). Complications included skin infections (n = 6), postoperative cutaneous fistula (n = 1), telecanthus (n = 4), diplopia (n = 3), nasal deformity (n = 2) and epiphora (n = 1). None of the patients suffered from postoperative CSF leak, meningitis or pneumocephalus. Six patients, all of whom had previously undergone frontal sinus obliteration, required revision surgery due to secondary mucocele formation. Statistical analysis using non-inferiority test reveal that cranialization of the frontal sinus is non-inferior to obliteration for preventing secondary mucocele formation (P<0.0001).

Conclusion

Cranialization of the frontal sinus appears to be a good option for prevention of secondary mucocele development after open excision of benign frontal sinus lesions.     

Histological and Functional Benefit Following Transplantation of Motor Neuron Progenitors to the Injured Rat Spinal Cord

Background

Motor neuron loss is characteristic of cervical spinal cord injury (SCI) and contributes to functional deficit.

Methodology/Principal Findings

In order to investigate the amenability of the injured adult spinal cord to motor neuron differentiation, we transplanted spinal cord injured animals with a high purity population of human motor neuron progenitors (hMNP) derived from human embryonic stem cells (hESCs). In vitro, hMNPs displayed characteristic motor neuron-specific markers, a typical electrophysiological profile, functionally innervated human or rodent muscle, and secreted physiologically active growth factors that caused neurite branching and neuronal survival. hMNP transplantation into cervical SCI sites in adult rats resulted in suppression of intracellular signaling pathways associated with SCI pathogenesis, which correlated with greater endogenous neuronal survival and neurite branching. These neurotrophic effects were accompanied by significantly enhanced performance on all parameters of the balance beam task, as compared to controls. Interestingly, hMNP transplantation resulted in survival, differentiation, and site-specific integration of hMNPs distal to the SCI site within ventral horns, but hMNPs near the SCI site reverted to a neuronal progenitor state, suggesting an environmental deficiency for neuronal maturation associated with SCI.

Conclusions/Significance

These findings underscore the barriers imposed on neuronal differentiation of transplanted cells by the gliogenic nature of the injured spinal cord, and the physiological relevance of transplant-derived neurotrophic support to functional recovery.     

TLR 2 and 4 Responsiveness from Isolated Peripheral Blood Mononuclear Cells from Rats and Humans as Potential Chronic Pain Biomarkers

Background

Chronic pain patients have increased peripheral blood mononuclear cell Interkeukin-1β production following TLR2 and TLR4 simulation. Here we have used a human-to-rat and rat-to-human approach to further investigate whether peripheral blood immune responses to TLR agonists might be suitable for development as possible systems biomarkers of chronic pain in humans.

Methods and Results

Study 1: using a graded model of chronic constriction injury in rats, behavioral allodynia was assessed followed by in vitro quantification of TLR2 and TLR4 agonist-induced stimulation of IL-1β release by PBMCs and spinal cord tissues (n = 42; 6 rats per group). Statistical models were subsequently developed using the IL-1β responses, which distinguished the pain/no pain states and predicted the degree of allodynia. Study 2: the rat-derived statistical models were tested to assess their predictive utility in determining the pain status of a published human cohort that consists of a heterogeneous clinical pain population (n = 19) and a pain-free population (n = 11). The predictive ability of one of the rat models was able to distinguish pain patients from controls with a ROC AUC of 0.94. The rat model was used to predict the presence of pain in a new chronic pain cohort and was able to accurately predict the presence of pain in 28 out of the 34 chronic pain participants.

Conclusions

These clinical findings confirm our previous discoveries of the involvement of the peripheral immune system in chronic pain. Given that these findings are reflected in the prospective graded rat data, it suggests that the TLR response from peripheral blood and spinal cord were related to pain and these clinical findings do indeed act as system biomarkers for the chronic pain state. Hence, they provide additional impetus to the neuroimmune interaction to be a drug target for chronic pain.     

High Levels of Both n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids in Cord Serum Phospholipids Predict Allergy Development

Background

Long-chain polyunsaturated fatty acids (LCPUFAs) reduce T-cell activation and dampen inflammation. They might thereby counteract the neonatal immune activation and hamper normal tolerance development to harmless environmental antigens. We investigated whether fatty acid composition of cord serum phospholipids affects allergy development up to age 13 years.

Methods

From a population-based birth-cohort born in 1996/7 and followed until 13 years of age (n = 794), we selected cases with atopic eczema (n = 37) or respiratory allergy (n = 44), as well as non-allergic non-sensitized controls (n = 48) based on diagnosis at 13 years of age. Cord and maternal sera obtained at delivery from cases and controls were analysed for proportions of saturated, monounsaturated and polyunsaturated fatty acids among serum phospholipids.

Results

The cord serum phospholipids from subject who later developed either respiratory allergy or atopic eczema had significantly higher proportions of 5/8 LCPUFA species, as well as total n-3 LCPUFA, total n-6 LCPUFA and total LCPUFA compared to cord serum phospholipids from controls who did not develop allergy (P<0.001 for all comparisons). Conversely, individuals later developing allergy had lower proportion of the monounsaturated fatty acid 18∶1n-9 as well as total MUFA (p<0.001) among cord serum phospholipids. The risk of respiratory allergy at age 13 increased linearly with the proportion of n-3 LCPUFA (P_trend<0.001), n-6 LCPUFA (P_trend = 0.001), and total LCPUFA (P_trend<0.001) and decreased linearly with the proportions of total MUFA (P_trend = 0.025) in cord serum phospholipids. Furthermore, Kaplan-Meier estimates of allergy development demonstrated that total LCPUFA proportion in cord serum phospholipids was significantly associated with respiratory allergy (P = 0.008) and sensitization (P = 0.002), after control for sex and parental allergy.

Conclusion

A high proportion of long-chain PUFAs among cord serum phospholipids may predispose to allergy development. The mechanism is unknown, but may involve dampening of the physiologic immune activation in infancy needed for proper maturation of the infant''s immune system.     

Granulocyte Colony-Stimulating Factor (G-CSF) Protects Oligpdendrocyte and Promotes Hindlimb Functional Recovery after Spinal Cord Injury in Rats

Background

Granulocyte colony-stimulating factor (G-CSF) is a protein that stimulates differentiation, proliferation, and survival of cells in the granulocytic lineage. Recently, a neuroprotective effect of G-CSF was reported in a model of cerebral infarction and we previously reported the same effect in studies of murine spinal cord injury (SCI). The aim of the present study was to elucidate the potential therapeutic effect of G-CSF for SCI in rats.

Methods

Adult female Sprague-Dawley rats were used in the present study. Contusive SCI was introduced using the Infinite Horizon Impactor (magnitude: 200 kilodyne). Recombinant human G-CSF (15.0 µg/kg) was administered by tail vein injection at 1 h after surgery and daily the next four days. The vehicle control rats received equal volumes of normal saline at the same time points.

Results

Using a contusive SCI model to examine the neuroprotective potential of G-CSF, we found that G-CSF suppressed the expression of pro-inflammatory cytokine (IL-1 beta and TNF- alpha) in mRNA and protein levels. Histological assessment with luxol fast blue staining revealed that the area of white matter spared in the injured spinal cord was significantly larger in G-CSF-treated rats. Immunohistochemical analysis showed that G-CSF promoted up-regulation of anti-apoptotic protein Bcl-Xl on oligpodendrocytes and suppressed apoptosis of oligodendrocytes after SCI. Moreover, administration of G-CSF promoted better functional recovery of hind limbs.

Conclusions

G-CSF protects oligodendrocyte from SCI-induced cell death via the suppression of inflammatory cytokines and up-regulation of anti-apoptotic protein. As a result, G-CSF attenuates white matter loss and promotes hindlimb functional recovery.     

Renal Involvement in Non-Hodgkin Lymphoma: Proven by Renal Biopsy

Aims

To determine the spectrum of renal lesions in patients with kidney involvement in non-Hodgkin''s lymphoma (NHL) by renal biopsy.

Methods

The clinical features and histological findings at the time of the renal biopsy were assessed for each patient.

Results

We identified 20 patients with NHL and renal involvement, and the diagnosis of NHL was established following the kidney biopsy in 18 (90%) patients. The types of NHL include the following: chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 8), diffuse large B-cell lymphoma (n = 4), T/NK cell lymphoma (n = 3), lymphoplasmacytic lymphoma (n = 2), cutaneous T-cell lymphoma (n = 1), mucosa-associated lymphoid tissue lymphoma (n = 1) and mantle cell lymphoma (n = 1). All presented with proteinuria, and 15 patients had impaired renal function. The pathological findings included (1) membranoproliferative glomerulonephritis-like pattern in seven patients; (2) crescent glomerulonephritis in four; (3) minimal-change disease in three, and glomeruli without specific pathological abnormalities in three; (4) intraglomerular large B-cell lymphoma in one; (5) intracapillary monoclonal IgM deposits in one; (6) primary diffuse large B-cell lymphoma of the kidneys in one; and (7) lymphoma infiltration of the kidney in eight patients.

Conclusion

A wide spectrum of renal lesions can be observed in patients with NHL, and NHL may be first proven by renal biopsies for evaluation of kidney injury or proteinuria. Renal biopsy is necessary to establish the underlying cause of renal involvement in NHL.     

The Metabolomic Profile of Umbilical Cord Blood in Neonatal Hypoxic Ischaemic Encephalopathy

Background

Hypoxic ischaemic encephalopathy (HIE) in newborns can cause significant long-term neurological disability. The insult is a complex injury characterised by energy failure and disruption of cellular homeostasis, leading to mitochondrial damage. The importance of individual metabolic pathways, and their interaction in the disease process is not fully understood. The aim of this study was to describe and quantify the metabolomic profile of umbilical cord blood samples in a carefully defined population of full-term infants with HIE.

Methods and Findings

The injury severity was defined using both the modified Sarnat score and continuous multichannel electroencephalogram. Using these classification systems, our population was divided into those with confirmed HIE (n = 31), asphyxiated infants without encephalopathy (n = 40) and matched controls (n = 71). All had umbilical cord blood drawn and biobanked at −80°C within 3 hours of delivery. A combined direct injection and LC-MS/MS assay (AbsolutIDQ p180 kit, Biocrates Life Sciences AG, Innsbruck, Austria) was used for the metabolomic analyses of the samples. Targeted metabolomic analysis showed a significant alteration between study groups in 29 metabolites from 3 distinct classes (Amino Acids, Acylcarnitines, and Glycerophospholipids). 9 of these metabolites were only significantly altered between neonates with Hypoxic ischaemic encephalopathy and matched controls, while 14 were significantly altered in both study groups. Multivariate Discriminant Analysis models developed showed clear multifactorial metabolite associations with both asphyxia and HIE. A logistic regression model using 5 metabolites clearly delineates severity of asphyxia and classifies HIE infants with AUC = 0.92. These data describe wide-spread disruption to not only energy pathways, but also nitrogen and lipid metabolism in both asphyxia and HIE.

Conclusion

This study shows that a multi-platform targeted approach to metabolomic analyses using accurately phenotyped and meticulously biobanked samples provides insight into the pathogenesis of perinatal asphyxia. It highlights the potential for metabolomic technology to develop a diagnostic test for HIE.     

Epidemiology of Spinal Cord Injuries and Risk Factors for Complete Injuries in Guangdong,China: A Retrospective Study

Background

Spinal cord injuries are highly disabling and deadly injuries. Currently, few studies focus on non-traumatic spinal cord injuries, and there is little information regarding the risk factors for complete injuries. This study aims to describe the demographics and the injury characteristics for both traumatic and non-traumatic spinal cord injuries and to explore the risk factors for complete spinal cord injuries.

Methods

A retrospective study was performed by reviewing the medical records of 3,832 patients with spinal cord injuries who were first admitted to the sampled hospitals in Guangdong, China. The demographics and injury characteristics of the patients were described and compared between the different groups using the chi-square test. Logistic regression was conducted to analyze the risk factors for complete spinal cord injuries.

Results

The proportion of patients increased from 7.0% to 14.0% from 2003 to 2011. The male-to-female ratio was 3.0∶1. The major cause of spinal cord injuries was traffic accidents (21.7%). Many of the injured were workers (36.2%), peasants (22.8%), and unemployed people (13.9%); these occupations accounted for 72.9% of the total sample. A multivariate logistic regression model revealed that the OR (95% CI) for male gender compared to female gender was 1.25 (1.07–1.89), the OR (95%CI) for having a spinal fracture was 1.56 (1.35–2.60), the OR (95%CI) for having a thoracic injury was 1.23 (1.10–2.00), and the OR (95%CI) for having complications was 2.47 (1.96–3.13).

Conclusion

The proportion of males was higher than the proportion of females. Workers, peasants and the unemployed comprised the high-risk occupational categories. Male gender, having a spinal fracture, having a thoracic injury, and having complications were the major risk factors for a complete injury. We recommend that preventive measures should focus on high-risk populations, such as young males.     

Transforaminal Decompression and Interbody Fusion in the Treatment of Thoracolumbar Fracture and Dislocation with Spinal Cord Injury

Study Design

A retrospective clinical study.

Objective

To evaluate the efficacy and safety of transforaminal decompression and interbody fusion in the treatment of thoracolumbar fracture and dislocation with spinal cord injury.

Methods

Twenty-six spinal cord injured patients with thoracolumbar fracture and dislocation were treated by transforaminal decompression and interbody fusion. The operation time, intraoperative blood loss, and complications were recorded; the Cobb angle and compressive rate (CR) of the anterior height of two adjacent vertebrae were measured; and the nerve injury was assessed according to sensory scores and motor scores of the American Spinal Injury Association (ASIA) standards for neurological classification of spinal cord injury.

Results

The operative time was 250±57 min, and intraoperative blood loss was 440±168 ml. Cerebrospinal leakage was detected and repaired during the operation in two patients. A total of 24 of 26 patients were followed up for more than 2 years. ASIA sensory scores and motor scores were improved significantly at 3 months and 6 months after operation; the Cobb angle and CR of the anterior height of two adjacent vertebrae were corrected and showed a significant difference at post-operation; and the values were maintained at 3 months after operation and the last follow-up.

Conclusion

We showed that transforaminal decompression together with interbody fusion is an alternative method to treat thoracolumbar fracture and dislocation.     

Cerebrospinal Fluid Interleukin-6 in Central Nervous System Inflammatory Diseases

Background

Interleukin (IL)-6 is recognised as an important cytokine involved in inflammatory diseases of the central nervous system (CNS).

Objective

To perform a large retrospective study designed to test cerebrospinal fluid (CSF) IL-6 levels in the context of neurological diseases, and evaluate its usefulness as a biomarker to help discriminate multiple sclerosis (MS) from other inflammatory neurological diseases (OIND).

Patients and Methods

We analyzed 374 CSF samples for IL-6 using a quantitative enzyme-linked immunosorbent assay. Groups tested were composed of demyelinating diseases of the CNS (DD, n = 117), including relapsing-remitting MS (RRMS, n = 65), primary progressive MS (PPMS, n = 11), clinically isolated syndrome (CIS, n = 11), optic neuritis (ON, n = 30); idiopathic transverse myelitis (ITM, n = 10); other inflammatory neurological diseases (OIND, n = 35); and non-inflammatory neurological diseases (NIND, n = 212). Differences between groups were analysed using Kruskal−Wallis test and Mann−Whitney U-test.

Results

CSF IL-6 levels exceeded the positivity cut-off of 10 pg/ml in 18 (51.4%) of the 35 OIND samples, but in only three (3.9%) of the 76 MS samples collected. CSF IL-6 was negative for all NIND samples tested (0/212). IL-6 cut-off of 10 pg/ml offers 96% sensitivity to exclude MS.

Conclusion

CSF IL-6 may help to differentiate MS from its major differential diagnosis group, OIND.     

Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS)

Background

There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Our objective was to evaluate the relative effectiveness of early (<24 hours after injury) versus late (≥24 hours after injury) decompressive surgery after traumatic cervical SCI.

Methods

We performed a multicenter, international, prospective cohort study (Surgical Timing in Acute Spinal Cord Injury Study: STASCIS) in adults aged 16–80 with cervical SCI. Enrolment occurred between 2002 and 2009 at 6 North American centers. The primary outcome was ordinal change in ASIA Impairment Scale (AIS) grade at 6 months follow-up. Secondary outcomes included assessments of complications rates and mortality.

Findings

A total of 313 patients with acute cervical SCI were enrolled. Of these, 182 underwent early surgery, at a mean of 14.2(±5.4) hours, with the remaining 131 having late surgery, at a mean of 48.3(±29.3) hours. Of the 222 patients with follow-up available at 6 months post injury, 19.8% of patients undergoing early surgery showed a ≥2 grade improvement in AIS compared to 8.8% in the late decompression group (OR = 2.57, 95% CI:1.11,5.97). In the multivariate analysis, adjusted for preoperative neurological status and steroid administration, the odds of at least a 2 grade AIS improvement were 2.8 times higher amongst those who underwent early surgery as compared to those who underwent late surgery (OR = 2.83, 95% CI:1.10,7.28). During the 30 day post injury period, there was 1 mortality in both of the surgical groups. Complications occurred in 24.2% of early surgery patients and 30.5% of late surgery patients (p = 0.21).

Conclusion

Decompression prior to 24 hours after SCI can be performed safely and is associated with improved neurologic outcome, defined as at least a 2 grade AIS improvement at 6 months follow-up.     

Technical Complications during Veno-Venous Extracorporeal Membrane Oxygenation and Their Relevance Predicting a System-Exchange – Retrospective Analysis of 265 Cases

Objectives

Technical complications are a known hazard in veno-venous extracorporeal membrane oxygenation (vvECMO). Identifying these complications and predictive factors indicating a developing system-exchange was the goal of the study.

Methods

Retrospective study on prospectively collected data of technical complications including 265 adult patients (Regensburg ECMO Registry, 2009-2013) with acute respiratory failure treated with vvECMO. Alterations in blood flow resistance, gas transfer capability, hemolysis, coagulation and hemostasis parameters were evaluated in conjunction with a system-exchange in all patients with at least one exchange (n = 83).

Results

Values presented as median (interquartile range). Patient age was 50(36–60) years, the SOFA score 11(8–14.3) and the Murray lung injury Score 3.33(3.3–3.7). Cumulative ECMO support time 3411 days, 9(6–15) days per patient. Mechanical failure of the blood pump (n = 5), MO (n = 2) or cannula (n = 1) accounted for 10% of the exchanges. Acute clot formation within the pump head (visible clots, increase in plasma free hemoglobin (frHb), serum lactate dehydrogenase (LDH), n = 13) and MO (increase in pressure drop across the MO, n = 16) required an urgent system-exchange, of which nearly 50% could be foreseen by measuring the parameters mentioned below. Reasons for an elective system-exchange were worsening of gas transfer capability (n = 10) and device-related coagulation disorders (n = 32), either local fibrinolysis in the MO due to clot formation (increased D-dimers [DD]), decreased platelet count; n = 24), or device-induced hyperfibrinolysis (increased DD, decreased fibrinogen [FG], decreased platelet count, diffuse bleeding tendency; n = 8), which could be reversed after system-exchange. Four MOs were exchanged due to suspicion of infection.

Conclusions

The majority of ECMO system-exchanges could be predicted by regular inspection of the complete ECMO circuit, evaluation of gas exchange, pressure drop across the MO and laboratory parameters (DD, FG, platelets, LDH, frHb). These parameters should be monitored in the daily routine to reduce the risk of unexpected ECMO failure.     

RASopathic Skin Eruptions during Vemurafenib Therapy

Purpose

Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.

Patients and Methods

Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.

Results

Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).

Conclusion

Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.     

Olprinone Attenuates the Acute Inflammatory Response and Apoptosis after Spinal Cord Trauma in Mice

Background

Olprinone hydrochloride is a newly developed compound that selectively inhibits PDE type III and is characterized by several properties, including positive inotropic effects, peripheral vasodilatory effects, and a bronchodilator effect. In clinical settings, olprinone is commonly used to treat congestive cardiac failure, due to its inotropic and vasodilating effects. The mechanism of these cardiac effects is attributed to increased cellular concentrations of cAMP. The aim of the present study was to evaluate the pharmacological action of olprinone on the secondary damage in experimental spinal cord injury (SCI) in mice.

Methodology/Principal Findings

Traumatic SCI is characterized by an immediate, irreversible loss of tissue at the lesion site, as well as a secondary expansion of tissue damage over time. Although secondary injury should be preventable, no effective treatment options currently exist for patients with SCI. Spinal cord trauma was induced in mice by the application of vascular clips (force of 24 g) to the dura via a four-level T5–T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, apoptosis, and locomotor disturbance. Olprinone treatment (0.2 mg/kg, i.p.) 1 and 6 h after the SCI significantly reduced: (1) the degree of spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) nitrotyrosine formation, (4) pro-inflammatory cytokines, (5) NF-κB expression, (6) p-ERK1/2 and p38 expression and (7) apoptosis (TUNEL staining, FAS ligand, Bax and Bcl-2 expression). Moreover, olprinone significantly ameliorated the recovery of hind-limb function (evaluated by motor recovery score).

Conclusions/Significance

Taken together, our results clearly demonstrate that olprinone treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.     

Human Neural Stem Cells Differentiate and Promote Locomotor Recovery in an Early Chronic Spinal coRd Injury NOD-scid Mouse Model

Background

Traumatic spinal cord injury (SCI) results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns) were prospectively isolated based on fluorescence-activated cell sorting for a CD133⁺ and CD24^−/lo population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.

Methods and Findings

hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein.

Conclusions

The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the “window of opportunity” for intervention.