Dynamic Autoregulatory Response After Aneurysmal Subarachnoid Hemorrhage and Its Relation to Angiographic Vasospasm and Clinical Outcome.

BACKGROUND: Impaired cerebral autoregulation (CA) is increasingly recognized to contribute to sequelae after aneurysmal subarachnoid hemorrhage (SAH). The current study characterizes the course of the dynamic autoregulation index (ARI) during the first 8 days after SAH and its coherence with angiographic vasospasm (VS) and clinical outcome. METHODS: Fifty-one patients with SAH were prospectively included within 48 h after the ictus. The ARI was determined daily for each hemisphere with the thigh cuff test. The degree of cerebral VS was evaluated based on a baseline digital subtraction angiography (DSA) after the ictus and a follow-up DSA on day 8. The clinical outcome was determined by the Modified Rankin Scale (mRS), the Glasgow Outcome Scale Extended (GOSE), and the National Institute of Health Stroke Scale (NIHSS) at discharge from the intensive care unit. RESULTS: Impaired CA significantly correlated with unfavorable clinical outcome scores (mRS, p = 0.0021; GOSE, p = 0.0027; NIHSS, p = 0.0091). ARI-values of patients with a favorable clinical outcome (mRS 0-3) showed a significant improvement during the first 8 days (+0.1964/day; p = 0.0148) compared to a significant decrease of ARI-values in patients with an unfavorable clinical outcome (-0.2976/day; p = 0.0182). The degree of CA impairment significantly correlated with the severity of VS in the middle cerebral artery (p = 0.0184). CONCLUSIONS: Early deterioration of CA significantly correlates with unfavorable clinical outcome and severity of angiographic vasospasm. Dynamic CA measurements might represent an important tool in stratifying therapy guidelines in patients after SAH.

Missing relationship of moyamoya and persistent primitive artery in Europeans. Another distinctive feature or artifact?

PURPOSE: Previous studies found higher incidence of persistent primitive arteries in Asian moyamoya (MM) patients than in the general population, which was thought to be a characteristic trait of the MM entity in general. We analyzed incidence of persistent primitive arteries and demographics of patients with European MM treated in one single center. First, we compared our large dataset to existing literature and second, we raised the question whether European MM demonstrates similar high prevalence of persistent primitive arteries as it was previously presented within Asian MM. METHODS: All European MM on whom revascularization surgery was performed from 1999 to 2013 were included. Demographics and associated diseases were obtained by retrospective chart review. Two independent readers evaluated 122 MM angiograms to determine the occurrence of persistent primitive arteries as well as the Suzuki score. RESULTS: We identified 112 cases with MM disease, 10 with MM syndrome. Mean age at time of diagnosis was 38.2 (range 6-64 years); a peak incidence in early childhood was not observed. Ninety (73.8%) were women, associated systemic diseases were found in four patients. Seven cases (5.7%) presented with unilaterally affected vessels. The majority of patients (71; 58.2%) were graded Suzuki Score 3. One 14-year-old boy with moyamoya presented with a primitive trigeminal artery (0.89%). CONCLUSIONS: We did not find a bimodal age distribution, but only a second peak during adulthood. Unlike previous studies on Asian moyamoya patients, our collective does not exhibit a higher prevalence of persistent primitive arteries than the normal population.

Vagal stimulation in brain dead donor rats decreases chronic allograft nephropathy in recipients.

BACKGROUND: Although it has been shown that a vagus nerve stimulation of brain dead (BD) donors leads to an improvement of renal function in recipients in an acute allograft rejection model, its influence on chronic allograft nephropathy is still unknown. In the present study, we assessed the influence of donor vagus nerve stimulation on survival, renal function and histology in a chronic allograft model. METHODS: Brain death was induced in Fisher rats, and electro-stimulation of the vagus nerve was applied in one group (BD + vagus) during the whole course of BD (6 h). Unstimulated BD Fisher donor rats served as controls. Allogeneic Lewis rats were used as recipients and no immunosuppressive medication was administered. Blood and urine samples were collected every second week. Banff classification was assessed from harvested allografts. RESULTS: Vagal stimulation of BD donors resulted in an improved survival of recipients. Long-term renal function was significantly better in these recipients as reflected by improved creatinine clearance. Banff classification revealed significantly reduced vasculopathy and less tubulopathy in the BD + vagus group. CONCLUSIONS: In conclusion, our data demonstrate a long-lasting beneficial effect of vagus nerve stimulation in BD donors on the renal transplantation outcome. Hence, activation of the cholinergic anti-inflammatory pathway in BD donors may represent a novel therapeutic modality to reduce chronic allograft nephropathy without any side effects for the recipient.

Severe Burn Injuries - The Day the Sodium Starts Rising.

BACKGROUND/AIM: The current study was designed to evaluate the etiologies of hypernatremic episodes in patients with severe burn injuries in comparison to critically ill non-burn patients. PATIENTS AND METHODS: The retrospective data acquisition was limited to the first 14 days and to patients with at least 20% total body surface area (TBSA) 2nd degree burn injuries or more than 10% TBSA when including areas of 3rd degree burn injuries. The results were compared to the results of a previously published study that analyzed the risk factors for hypernatremia in 390 non-burn intensive care unit patients. RESULTS: In total, 120 patients with a total of 50 hypernatremic episodes were included. Compared to non-burn injury patients, no significant differences were detectable except for a lower rate of hypokalemia and a higher rate of mechanical ventilation. The main trigger for hypernatremic episodes was the loss of free water, while 24% of the hypernatremic episodes seemed to be at least partly triggered by a surplus sodium influx. Patients with hypernatremic episodes had a significantly higher mortality rate. However, in none of the cases was hypernatremia the decisive cause of death. CONCLUSION: Besides the unique phenomenon of high volume internal and external volume shifts, the overall risk factors and etiologies of hypernatremia in patients with severe burn injury do not seem to significantly differ from other ICU patient collectives. Remarkably, a surplus of sodium influx and therefore a modifiable factor besides the specific burn injury volume resuscitation had an impact on the hypernatremic episodes in 24% of cases.

Antibiotics in patients with severe burn injury-A modifiable variable in hypernatremia etiology.

INTRODUCTION: Hypernatremia is a common problem among patients with severe burn injuries and seems to be associated with an unfavorable clinical outcome. The current study was designed to evaluate the impact of antibiotics with a high proportion of sodium on this phenomenon. METHODS: All admissions to our burn center from 01/2017 till 06/2023 were retrospectively screened. All patients aged >18 years which suffered from at least 20 % total body surface burned area (TBSA) 2nd degree burn injuries or more than 10 % TBSA when including areas of 3rd degree burn injuries were included. The course of the serum Na-level was analyzed from two days before till two days after the start of the antibiotic treatment. Ampicillin/sulbactam, cefazoline and piperacillin/tazobactam were classified as high-dose sodium antibiotics (HPS), meropenem and vancomycin as low-dose sodium antibiotics (LPS). RESULTS: 120 patients met the inclusion criteria. A significant increase of the serum Na was detectable in the HPS group on day 1 and 2 after initiating the antibiotic treatment (n = 64, day 1: 2,1 (SD 4,18) mmol/l, p < 0,001; day 2: 2,44 (SD 5,26) mmol/l, p < 0,001) while no significant changes were detectable in the LPS group (n = 21, day 1: 0,18 (SD 7,45) mmol/l, p = 0,91; day 2: -0,27 (SD 7,44) mmol/l, p = 0,87). This effect was further aggravated when analyzing only the HPS patients with a TBSA ≥30 % (n = 33; day 1: 2,93 (SD 4,68) mmol/l, p = 0,002; day 2: 3,41 (SD 5,9) mmol/l, p = 0,003). CONCLUSION: The amount of sodium in antibiotics seems to have a relevant impact on the serum Na during the early stages of severe burn injury. Therefore, this aspect should be taken into account when searching for the most appropriate antibiotic treatment for patients with severe burn injury, especially when being at acute risk for a clinical relevant hypernatremia.

UW is superior compared with HTK after prolonged preservation of renal grafts.

BACKGROUND: In recent clinical studies, the efficacy of histidine-tryptophan-ketoglutarate (HTK) in kidney transplantation was questioned. This study compares the efficacy of University of Wisconsin (UW) and HTK solutions on transplantation outcome. MATERIALS AND METHODS: Rat kidneys were preserved for different periods of cold ischemia (CIT). Heat capacity of the solutions, temperature of the grafts, renal function (RF), and histology were assessed before and after transplantation, respectively. RESULTS: After prolonged CIT, recipient survival was superior in the UW - (100%) compared with the HTK group (10%). In the latter, severe tubular necrosis, DNA damage, and renal inflammation were observed, reflected by an increased KIM-1, IL6, and P-selectin expression. CIT correlated negatively with RF in both groups. RF recovered significantly faster in the UW group. LDH-release and ATP depletion after cold storage of tubular cells were lower in UW than in HTK. Heat capacity was significantly higher for UW than for HTK. Accordingly, renal temperature was lower. CONCLUSIONS: Prolonged preservation in UW solution results in a better renal function and less tissue damage compared with HTK, possibly due to improved cooling and better cell viability of the graft. The use of HTK for renal allografts should therefore be reconsidered, particularly when CIT is expected to be long.

Impairment of Dynamic Pressure Autoregulation Precedes Clinical Deterioration after Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: This study was designed to evaluate the potential of the dynamic autoregulation index (ARI) to serve as an early warning system for an imminent clinical deterioration after subarachnoid hemorrhage (SAH). METHODS: All patients received a baseline digital subtraction angiography and a computed tomography (CT) prior to treatment. The clinical status, the ARI, and the transcranial Doppler (TCD) values were evaluated daily until discharge from the intensive care unit (ICU). A CT scan at least 10 days after the postictal event was used to determine the occurrence of delayed infarcts. RESULTS: 20 patients were prospectively included in the study. 3 refused further participation between days 2 and 3. Patients with no significant deteriorations of the clinical status and no proximal vasospasm (VS) in the middle cerebral artery (MCA)/delayed infarcts showed a significant positive linear regression of the ARI values in both hemispheres from day 1 till 11 (ARI right: 2.7 + .31/day, ARI left: 2.8 + .27/day; P < .01). All patients with angiographic VS of more than one-third in the MCA showed a corresponding drop of the ARI to values ≤1.7. The ARI drop occurred 2.5 (±1.3) days prior to significant deteriorations of the clinical status, increase of TCD values or the detection of angiographic cerebral VS/delayed infarcts in the corresponding hemispheres. CONCLUSION: The results demonstrate the capability of the ARI to serve as a reliable early warning system after SAH. Further trials with larger study populations are needed to validate these promising preliminary data.

Occurrence of discal and non-discal changes after sequestrectomy alone versus sequestrectomy and implantation of an anulus closure device.

Sequestrectomy alone represents a procedure for the treatment of lumbar disc herniation. For selected cases, an anulus closure device (ACD) can be implanted which may result in lower reoperation rates. However, comparative magnetic resonance imaging (MRI) changes and their clinical relevance of both procedures are unclear and have not been reported so far. Clinical and MRI data of patients after limited discectomy with ACD implantation (group ACD; N=45) and patients after sequestrectomy alone (group S; N=40) with primary lumbar disc herniation were compared retrospectively. Pain intensity on the visual analogue pain scale (VAS), oswestry disability index (ODI) or the patient satisfaction index (PSI) were collected. Disc signal intensity, Modic type changes, endplate reactions, anular tears and reherniations were investigated using MRI before and <18months postoperative. Morphologic changes were correlated with clinical outcome. There was no difference in VAS back, VAS leg or ODI/PSI after the operation although group S showed significantly more reherniations in MRI. The overall rate of repeated surgery at the same level was similar with a trend in favour of the ACD group (P=0.729). Significantly more patients of the ACD group experienced endplate erosions after surgery (P<0.001). Both groups experienced progression of disc signal intensity, Modic type changes, and anular tears with most MRI signs being without clinical relevance. ACD implantation is associated with a significantly lower reherniation rate in MRI but showed a significantly higher rate of endplate erosions. The structural changes do not appear to be clinically relevant.

The neglected need for psychological intervention in patients suffering from incidentally discovered intracranial aneurysms.

OBJECTIVES: Previous studies demonstrated a conspicuously elevated rate of psychiatric disorders in patients with incidental intracranial aneurysms. This study was designed to analyze the impact of this observation on the post-interventional rates of PTSD, depressions and anxiety disorders in this collective. METHODS: Physically unaffected iA patients with an unremarkable medical history were included in this two center study. Pre-interventional psychiatric histories, rates of post-interventional depressions, subjective trauma, PTSD, and pre-interventional fears were determined by questionnaires (Beck Depression Inventory (BDI), Impact of Event Scale (IES), civilian Post-traumatic-Stress-Disorder (PTSD) Check List (PCL-C)). Benign meningioma (M) patients served as controls. RESULTS: 58 M and 45 iA patients were enrolled. Significantly higher rates of PTSD, elevated trauma scores, and moderate/severe depressions (PTSD: p=0.0017; IES: p=0.0038; BDI: p=0.0301) were demonstrated in the iA collective. After excluding patients with a positive pre-interventional psychiatric history those differences were not reproducible. 70% of the iA patients reported an improvement of their unspecific pre-interventional symptoms, while 30% would have rated a psychological consultation as helpful. CONCLUSION: The data identifies the early psychological consultation as a relevant and by affected patients accepted treatment modification when trying to improve the outcome after treatment of incidental aneurysms.

The Preinterventional Psychiatric History as a Major Predictor for a Reduced Quality of Life After Treatment of Unruptured Intracranial Aneurysms.

BACKGROUND: A significantly increased rate of positive preinterventional psychiatric histories in the unruptured aneurysm collective was demonstrated previously. The current study was designed to analyze the influence of the preinterventional psychiatric status on the outcome after treatment of unruptured intracranial aneurysms. METHODS: Patients treated due to meningioma World Health Organization °I and unruptured intracranial aneurysms in 2 German neurosurgical centers between 2007 and 2013 were screened for exclusion criteria including malignant/chronic diseases, recurrence of the tumor/aneurysm, and neurologic deficits among others. The preinterventional psychiatric histories and the rates of postinterventional headaches, sleeping disorders, symptoms of chronic fatigue syndrome, and quality of life (QOL) were determined by questionnaires that were mailed to the patients in a printed version. RESULTS: A total of 58 M patients and 45 iA patients who met the inclusion criteria returned the questionnaires; 10 M (17.2%) and 17 iA patients (37.8%) had a positive psychiatric history. The overall Incidental aneurysm collective demonstrated significantly lower overall QOL scores (P = 0.003) and significant greater rates of chronic fatigue syndrome (P = 0.009) compared with the M collective. After we excluded all patients with positive pre-interventional psychiatric histories, those differences were no longer reproducible. Subjectively, the patients did not realize any significant changes in their QOL after successful aneurysm treatment. CONCLUSIONS: The results of the current study demonstrate the importance of taking the preinterventional psychiatric history into considerations when evaluating the outcome after unruptured aneurysm treatment. The unfavorable outcome of the aneurysm group seems to be caused by factors that are not related the aneurysm diagnosis or treatment itself.

The spontaneous arterial blood pressure rise after aneurysmal subarachnoid hemorrhage - a biphasic phenomenon.

OBJECTIVES: A spontaneous blood pressure (BP) rise is frequently observed after aneurysmal subarachnoid hemorrhage (aSAH). The current study was designed to characterize the time course of this BP rise and its relation to clinical and radiological parameters. METHODS: The diastolic (DBP), mean (MAP), and systolic (SBP) BP values were determined in 61 aSAH patients from day 0 to 9. The patient's initial status was evaluated by the world federation of neurological surgeons scale and the Hijdra scale. The clinical outcome was quantified by the modified Rankin Scale, the Glasgow Outcome Scale Extended, and the National Institute of Health Stroke Scale. The degree of proximal and global vasospasm was calculated by comparison of the baseline angiography on day 0 and the control angiography on day 8. Furthermore, the influence of propofol and norepinephrine application was analyzed. RESULTS: DBP, MAP, and SBP demonstrated an early rise in all patients from day 2 till 5 (p<0.001) and remained hypertensive until day 9. No significant correlation could be detected between this early BP rise and most clinical and radiological variables. From day 8 onwards, a divergence of the SBP courses was detected between patients with severe vs. non-severe global vasospasm. There was a secondary, norepinephrine independent SBP rise in patients with severe global vasospasm that significantly correlated with the initial Hijdra-scale and an unfavorable clinical outcome. CONCLUSIONS: The results demonstrate a biphasic BP course with a uniform early BP rise in all patients and an additional delayed SBP rise in patients with severe global vasospasm.

Sonographic examination of the median nerve in dialysis patients and after renal transplantation.

OBJECTIVE: Patients with renal insufficiency are predisposed to develop CTS (carpal tunnel syndrome). In particular, long-term dialysis seems to contribute to changes in median nerve texture which lead to an increased risk for CTS. The current study was designed to evaluate if these structural changes can be detected by HRS (high-resolution sonography). Additionally, the current study aimed to determine if changes are reversible after termination of dialysis. METHODS: Fifty patients (98 hands) were included in the study. The study population was subdivided into three groups: patients without any history of renal disease (H, n = 20), patients with long-term dialysis (D, n = 10), and patients after renal transplantation (TX, n = 20). None of the patients had any clinical symptoms for a median nerve compression syndrome. The CSA (cross-sectional area) of the median nerve was evaluated both 12 cm proximally of the carpal tunnel inlet and directly at the carpal tunnel inlet. The ratio of those two values, the WFR (wrist forearm ratio), was calculated and analyzed. RESULTS: The CSA demonstrated significantly higher values in dialysis (D) and transplanted (TX) patients compared to the healthy (H) control group (P < 0.001). No significant differences were detectable between the D and TX groups. Specifically, there was no significant difference in the WFR. CONCLUSION: Patients with chronic renal disease demonstrate significantly higher CSA values compared to their healthy counterparts. Termination of dialysis does not seem to reverse these morphological changes.

Smart trepanation system: preclinical analysis of safety, efficiency, and user satisfaction.

BACKGROUND/OBJECTIVE: To reduce the risk of dural tears during craniotomies and the associated complications, we developed the Smart Trepanation System (STS) that provides an image- and sensor-based automatic control of the cutting depth of a manually guided soft tissue preserving saw. This article presents the results of an initial user-centered evaluation. METHODS: Interactive usability tests with six neurosurgeons were conducted. Resection time and accuracy were recorded in a standardized laboratory setting and compared with a standard craniotome. User satisfaction and subjective workload were assessed using the National Aeronautics and Space Administration Task Load Index scale and a questionnaire regarding intuitiveness, fault tolerance, learnability, and user satisfaction. RESULTS: The mean resection time after getting used to the STS was 36.4 ± 9.2 second longer than with the conventional craniotome. All task load indexes except for the temporal demand were rated higher when using the STS, but all were rated smaller than 3 and thus classified as only a small extra task load. The questionnaire showed that the system is not only feasible but also accepted by surgeons and that the user interaction seems to be designed as intuitive, fault tolerant, and easy to learn. CONCLUSION: Although the conventional craniotome seems to perform a trepanation faster and with less workload, the advantage of performing a dura-preserving trepanation with significantly smaller cutting gaps outweighs those disadvantages. For validation of those promising in vitro results, further studies have to be conducted in a fresh human cadaver model or in a clinical setting.

Imbalanced protein expression patterns of anabolic, catabolic, anti-catabolic and inflammatory cytokines in degenerative cervical disc cells: new indications for gene therapeutic treatments of cervical disc diseases.

Degenerative disc disease (DDD) of the cervical spine is common after middle age and can cause loss of disc height with painful nerve impingement, bone and joint inflammation. Despite the clinical importance of these problems, in current publications the pathology of cervical disc degeneration has been studied merely from a morphologic view point using magnetic resonance imaging (MRI), without addressing the issue of biological treatment approaches. So far a wide range of endogenously expressed bioactive factors in degenerative cervical disc cells has not yet been investigated, despite its importance for gene therapeutic approaches. Although degenerative lumbar disc cells have been targeted by different biological treatment approaches, the quantities of disc cells and the concentrations of gene therapeutic factors used in animal models differ extremely. These indicate lack of experimentally acquired data regarding disc cell proliferation and levels of target proteins. Therefore, we analysed proliferation and endogenous expression levels of anabolic, catabolic, ant-catabolic, inflammatory cytokines and matrix proteins of degenerative cervical disc cells in three-dimensional cultures. Preoperative MRI grading of cervical discs was used, then grade III and IV nucleus pulposus (NP) tissues were isolated from 15 patients, operated due to cervical disc herniation. NP cells were cultured for four weeks with low-glucose in collagen I scaffold. Their proliferation rates were analysed using 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide. Their protein expression levels of 28 therapeutic targets were analysed using enzyme-linked immunosorbent assay. During progressive grades of degeneration NP cell proliferation rates were similar. Significantly decreased aggrecan and collagen II expressions (P<0.0001) were accompanied by accumulations of selective catabolic and inflammatory cytokines (disintegrin and metalloproteinase with thrombospondin motifs 4 and 5, matrix metalloproteinase 3, interleukin-1ß, interleukin-1 receptor) combined with low expression of anti-catabolic factor (metalloproteinase inhibitor 3) (P<0.0001). This study might contribute to inhibit inflammatory catabolism of cervical discs.

N-octanoyl dopamine treatment of endothelial cells induces the unfolded protein response and results in hypometabolism and tolerance to hypothermia.

AIM: N-acyl dopamines (NADD) are gaining attention in the field of inflammatory and neurological disorders. Due to their hydrophobicity, NADD may have access to the endoplasmic reticulum (ER). We therefore investigated if NADD induce the unfolded protein response (UPR) and if this in turn influences cell behaviour. METHODS: Genome wide gene expression profiling, confirmatory qPCR and reporter assays were employed on human umbilical vein endothelial cells (HUVEC) to validate induction of UPR target genes and UPR sensor activation by N-octanoyl dopamine (NOD). Intracellular ATP, apoptosis and induction of thermotolerance were used as functional parameters to assess adaptation of HUVEC. RESULTS: NOD, but not dopamine dose dependently induces the UPR. This was also found for other synthetic NADD. Induction of the UPR was dependent on the redox activity of NADD and was not caused by selective activation of a particular UPR sensor. UPR induction did not result in cell apoptosis, yet NOD strongly impaired cell proliferation by attenuation of cells in the S-G2/M phase. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. These cells were significantly more resistant to cold inflicted injury. CONCLUSIONS: We provide for the first time evidence that NADD induce the UPR in vitro. It remains to be assessed if UPR induction is causally associated with hypometabolism and thermotolerance. Further pharmacokinetic studies are warranted to address if the NADD concentrations used in vitro can be obtained in vivo and if this in turn shows therapeutic efficacy.

Surgical management of basilar artery laceration caused by transorbital penetrating injury: case report.

Transorbital penetrating injuries are rare and present with a heterogeneity of intracranial injury patterns that require individualized therapeutic procedures. In this report, we describe the case of a distal basilar artery laceration in a 16-month-old boy caused by accidental transorbital penetration with a pencil. Surgical removal of the pencil was performed, but hemostasis could only be achieved by clipping the impaired vessel. Adequate diagnostics and an individualized surgical strategy are necessary to deal with these life-threatening injuries.

A combinatorial relative mass value evaluation of endogenous bioactive proteins in three-dimensional cultured nucleus pulposus cells of herniated intervertebral discs: identification of potential target proteins for gene therapeutic approaches.

Painful degenerative disc diseases have been targeted by different biological treatment approaches. Nucleus pulposus (NP) cells play a central role in intervertebral disc (IVD) maintenance by orchestrating catabolic, anabolic and inflammatory factors that affect the extracellular matrix. IVD degeneration is associated with imbalances of these factors, resulting in a catabolic inflammatory metabolism. Therefore, accurate knowledge about their quantity and quality with regard to matrix synthesis is vital for a rational gene therapeutic approach. NP cells were isolated from 63 patients operated due to lumbar disc herniation (mean age 56 / range 29 - 84 years). Then, three-dimensional culture with low-glucose was completed in a collagen type I scaffold for four weeks. Subsequently cell proliferation evaluation was performed using 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide and intracellular concentration of 28 endogenously expressed anabolic, catabolic, inflammatory factors and relevant matrix proteins was determined by enzyme-linked immunosorbent assay. Specimen-related grades of degeneration were confirmed by preoperative magnetic resonance imaging. Independent from gender, age and grade of degeneration proliferation rates remained similar in all groups of NP cells. Progressive grades of degeneration, however, showed a significant influence on accumulation of selective groups of factors such as disintegrin and metalloproteinase with thrombospondin motifs 4 and 5, matrix metalloproteinase 3, metalloproteinase inhibitor 1 and 2, interleukin-1ß and interleukin-1 receptor. Along with these changes, the key NP matrix proteins aggrecan and collagen II decreased significantly. The concentration of anabolic factors bone morphogenetic proteins 2, 4, 6 and 7, insulin-like growth factor 1, transforming growth factor beta 1 and 3, however, remained below the minimal detectable quantities. These findings indicate that progressive degenerative changes in NP may be problematic with regard to biologic treatment strategies. Hence, gene therapeutic interventions regulating relevant bioactive factors identified in this work might contribute to the development of regenerative treatment approaches for degenerative disc diseases.

The additional detrimental effects of cold preservation on transplantation-associated injury in kidneys from living and brain-dead donor rats.

BACKGROUND: Brain death and cold preservation are major alloantigen-independent risk factors for transplantation outcome. The present study was conducted to assess the influence of these factors on transplantation-associated injury independently or in combination. METHODS: Brain death was induced in F344 rats. Renal grafts were harvested after 6 hr and either directly transplanted in unilateral nephrectomized Lewis recipient or subjected to 24 hr of cold preservation in University of Wisconsin solution before implantation. Allografts obtained from living donor rats were also subjected to cold preservation or not. DNA damage was assessed before implantation by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining. Ten days after transplantation, renal histology was performed according to Banff '97 classification. The expressions of cytokines and adhesion molecules were analyzed by quantitative polymerase chain reaction. RESULTS: Cold preservation significantly increased the number of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling positive cells in renal allografts. Ten days after transplantation, histology revealed a higher degree of tubulitis and vasculitis scores when the grafts were subjected to cold storage. Vasculitis was aggravated when the graft was obtained from brain death (BD) donors. BD, but not cold preservation alone, was associated with papillary necrosis. This was more frequently observed after cold preservation. Immunohistology showed an increase in MHC class II+ cells after cold preservation. The combination of BD and cold preservation revealed a higher degree of VEGF and IL-10 expression. CONCLUSIONS: Our Study emphasizes that cold ischemia time should be limited when renal allografts from brain-dead donors are transplanted.