Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain.

Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI.

Concentration-dependent half-lives of polychlorinated biphenyl in sera from an occupational cohort.

Polychlorinated biphenyls (PCBs) are carcinogenic. Estimating PCB half-life in the body based on levels in sera from exposed workers is complicated by the fact that occupational exposure to PCBs was to commercial PCB products (such as Aroclors 1242 and 1254) comprised of varying mixtures of PCB congeners. Half-lives were estimated using sera donated by 191 capacitor manufacturing plant workers in 1976 during PCB use (1946-1977), and post-exposure (1979, 1983, and 1988). Our aims were to: (1) determine the role of covariates such as gender on the half-life estimates, and (2) compare our results with other published half-life estimates based on exposed workers. All serum PCB levels were adjusted for PCB background levels. A linear spline model with a single knot was used to estimate two separate linear equations for the first two serum draws (Equation A) and the latter two (Equation B). Equation A gave half-life estimates of 1.74 years and 6.01 years for Aroclor 1242 and Aroclor 1254, respectively. Estimates were 21.83 years for Aroclor 1242 and 133.33 years for Aroclor 1254 using Equation B. High initial body burden was associated with rapid PCB elimination in workers at or shortly after the time they were occupationally exposed and slowed down considerably when the dose reached background PCB levels. These concentration-dependent half-life estimates had a transition point of 138.57 and 34.78 ppb for Aroclor 1242 and 1254, respectively. This result will help in understanding the toxicological and epidemiological impact of exposure to PCBs in humans.

Intracranial hypertension: what additional information can be derived from ICP waveform after head injury?

OBJECTIVE: Although intracranial hypertension is one of the important prognostic factors after head injury, increased intracranial pressure (ICP) may also be observed in patients with favourable outcome. We have studied whether the value of ICP monitoring can be augmented by indices describing cerebrovascular pressure-reactivity and pressure-volume compensatory reserve derived from ICP and arterial blood pressure (ABP) waveforms. METHOD: 96 patients with intracranial hypertension were studied retrospectively: 57 with fatal outcome and 39 with favourable outcome. ABP and ICP waveforms were recorded. Indices of cerebrovascular reactivity (PRx) and cerebrospinal compensatory reserve (RAP) were calculated as moving correlation coefficients between slow waves of ABP and ICP, and between slow waves of ICP pulse amplitude and mean ICP, respectively. The magnitude of 'slow waves' was derived using ICP low-pass spectral filtration. RESULTS: The most significant difference was found in the magnitude of slow waves that was persistently higher in patients with a favourable outcome (p<0.00004). In patients who died ICP was significantly higher (p<0.0001) and cerebrovascular pressure-reactivity (described by PRx) was compromised (p<0.024). In the same patients, pressure-volume compensatory reserve showed a gradual deterioration over time with a sudden drop of RAP when ICP started to rise, suggesting an overlapping disruption of the vasomotor response. CONCLUSION: Indices derived from ICP waveform analysis can be helpful for the interpretation of progressive intracranial hypertension in patients after brain trauma.

Spare non-occupational HIV post-exposure prophylaxis by active contacting and testing of the source person.

OBJECTIVE: HIV-1 post-exposure prophylaxis (PEP) is frequently prescribed after exposure to source persons with an undetermined HIV serostatus. To reduce unnecessary use of PEP, we implemented a policy including active contacting of source persons and the availability of free, anonymous HIV testing ('PEP policy'). METHODS: All consultations for potential non-occupational HIV exposures i.e. outside the medical environment) were prospectively recorded. The impact of the PEP policy on PEP prescription and costs was analysed and modelled. RESULTS: Among 146 putative exposures, 47 involved a source person already known to be HIV positive and 23 had no indication for PEP. The remaining 76 exposures involved a source person of unknown HIV serostatus. Of 33 (43.4%) exposures for which the source person could be contacted and tested, PEP was avoided in 24 (72.7%), initiated and discontinued in seven (21.2%), and prescribed and completed in two (6.1%). In contrast, of 43 (56.6%) exposures for which the source person could not be tested, PEP was prescribed in 35 (81.4%), P &lt; 0.001. Upon modelling, the PEP policy allowed a 31% reduction of cost for management of exposures to source persons of unknown HIV serostatus. The policy was cost-saving for HIV prevalence of up to 70% in the source population. The availability of all the source persons for testing would have reduced cost by 64%. CONCLUSION: In the management of non-occupational HIV exposures, active contacting and free, anonymous testing of source persons proved feasible. This policy resulted in a decrease in prescription of PEP, proved to be cost-saving, and presumably helped to avoid unnecessary toxicity and psychological stress.

CD47 knockout mice exhibit improved recovery from spinal cord injury.

Recent data have implicated thrombospondin-1 (TSP-1) signaling in the acute neuropathological events that occur in microvascular endothelial cells (ECs) following spinal cord injury (SCI) (Benton et al., 2008b). We hypothesized that deletion of TSP-1 or its receptor CD47 would reduce these pathological events following SCI. CD47 is expressed in a variety of tissues, including vascular ECs and neutrophils. CD47 binds to TSP-1 and inhibits angiogenesis. CD47 also binds to the signal regulatory protein (SIRP)α and facilitates neutrophil diapedesis across ECs to sites of injury. After contusive SCI, TSP-1(-/-) mice did not show functional improvement compared to wildtype (WT) mice. CD47(-/-) mice, however, exhibited functional locomotor improvements and greater white matter sparing. Whereas targeted deletion of either CD47 or TSP-1 improved acute epicenter vascularity in contused mice, only CD47 deletion reduced neutrophil diapedesis and increased microvascular perfusion. An ex vivo model of the CNS microvasculature revealed that CD47(-/-)-derived microvessels (MVs) prominently exhibit adherent WT or CD47(-/-) neutrophils on the endothelial lumen, whereas WT-derived MVs do not. This implicates a defect in diapedesis mediated by the loss of CD47 expression on ECs. In vitro transmigration assays confirmed the role of SIRPα in neutrophil diapedesis through EC monolayers. We conclude that CD47 deletion modestly, but significantly, improves functional recovery from SCI via an increase in vascular patency and a reduction of SIRPα-mediated neutrophil diapedesis, rather than the abrogation of TSP-1-mediated anti-angiogenic signaling.

Brain Tissue Hypoxia is a Strong Predictor of Outcome after Severe Traumatic Brain Injury Independent from Elevated Intracranial Pressure

Introduction: Low brain tissue oxygen pressure (PbtO2) is associated with worse outcome in patients with severe traumatic brain injury (TBI). However, it is unclear whether brain tissue hypoxia is merely a marker of injury severity or a predictor of prognosis, independent from intracranial pressure (ICP) and injury severity. Hypothesis: We hypothesized that brain tissue hypoxia was an independent predictor of outcome in patients wih severe TBI, irrespective of elevated ICP and of the severity of cerebral and systemic injury. Methods: This observational study was conducted at the Neurological ICU, Hospital of the University of Pennsylvania, an academic level I trauma center. Patients admitted with severe TBI who had PbtO2 and ICP monitoring were included in the study. PbtO2, ICP, mean arterial pressure (MAP) and cerebral perfusion pressure (CPP = MAP-ICP) were monitored continuously and recorded prospectively every 30 min. Using linear interpolation, duration and cumulative dose (area under the curve, AUC) of brain tissue hypoxia (PbtO2 < 15 mm Hg), elevated ICP >20 mm Hg and low CPP <60 mm Hg were calculated, and the association with outcome at hospital discharge, dichotomized as good (Glasgow Outcome Score [GOS] 4-5) vs. poor (GOS 1-3), was analyzed. Results: A total of 103 consecutive patients, monitored for an average of 5 days, was studied. Brain tissue hypoxia was observed in 66 (64%) patients despite ICP was < 20 mm Hg and CPP > 60 mm Hg (72 +/- 39% and 49 +/- 41% of brain hypoxic time, respectively). Compared with patients with good outcome, those with poor outcome had a longer duration of brain hypoxia (1.7 +/- 3.7 vs. 8.3 +/- 15.9 hrs, P<0.01), as well as a longer duration (11.5 +/- 16.5 vs. 21.6 +/- 29.6 hrs, P=0.03) and a greater cumulative dose (56 +/- 93 vs. 143 +/- 218 mm Hg*hrs, P<0.01) of elevated ICP. By multivariable logistic regression, admission Glasgow Coma Scale (OR, 0.83, 95% CI: 0.70-0.99, P=0.04), Marshall CT score (OR 2.42, 95% CI: 1.42-4.11, P<0.01), APACHE II (OR 1.20, 95% CI: 1.03-1.43, P=0.03), and the duration of brain tissue hypoxia (OR 1.13; 95% CI: 1.01-1.27; P=0.04) were all significantly associated with poor outcome. No independent association was found between the AUC for elevated ICP and outcome (OR 1.01, 95% CI 0.97-1.02, P=0.11) in our prospective cohort. Conclusions: In patients with severe TBI, brain tissue hypoxia is frequent, despite normal ICP and CPP, and is associated with poor outcome, independent of intracranial hypertension and the severity of cerebral and systemic injury. Our findings indicate that PbtO2 is a strong physiologic prognostic marker after TBI. Further study is warranted to examine whether PbtO2-directed therapy improves outcome in severely head-injured patients .

A selective nociceptive block is not sufficient to prevent central changes after peripheral nerve injury

Background: Providing analgesia without suppressing motor or sensory function is a challenge for regional anesthesia and postoperative pain management. Resiniferatoxin (RTX), an ultrapotent agonist for transient receptor potential subtype-1 (TRPV1) can produce this selective blockade, as TRPV1 is selectively expressed on nociceptors. Futhermore, after peripheral nerve injury, spontaneous ectopic activity arises from all types of nerve fibers that can affect spinal neurons and glial cells. The goal of the present experiment is to determine whether spontaneous activity generated in C-fibers or in both A&C-fibers is required for microglia activation. Method: We applied RTX (0.01%) or bupivacaine microspheres to the sciatic nerve of rats to block the conduction of C-fibers or A&C-fibers, respectively, before spared nerve injury (SNI). Behavior was tested and all the rats were sacrificed 2 days later; immunohistochemistry was performed on their spinal cord for mitogen-activated protein kinase (MAPK) p38, bromodeoxyuridine (BrdU, marker of proliferation) and Iba1 (microglial marker). Result: At day 2 after SNI robust mechanical allodynia and p38 activation in spinal microglia were documented. There was also a substantial cell proliferation in the spinal cord, all proliferating cells (BrdU+) being microglia (Iba1+). RTX blocked heat sensitivity and produced heat hypoalgesia without affecting mechanical allodynia and motor function. Microglial proliferation and p38 activation in the spinal cord were not affected by RTX (p >0.05). In contrast, a complete sensory and motor blockade was seen with bupivacaine which also significantly inhibited p38 activation and microglial proliferation in the spinal cord (p <0.05). Conclusion: We conclude that (1) RTX can provide a selective nociceptive blockade but that (2) blocking only nociceptive fibers does not impair the development of mechanical allodynia and microglia activation. Therefore (3) if microglia activation is important for chronic pain development then specific nociceptive blockade won't be sufficient to prevent it.

Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury.

BACKGROUND: After peripheral nerve injury, spontaneous ectopic activity arising from the peripheral axons plays an important role in inducing central sensitization and neuropathic pain. Recent evidence indicates that activation of spinal cord microglia also contributes to the development of neuropathic pain. In particular, activation of p38 mitogen-activated protein kinase (MAPK) in spinal microglia is required for the development of mechanical allodynia. However, activity-dependent activation of microglia after nerve injury has not been fully addressed. To determine whether spontaneous activity from C- or A-fibers is required for microglial activation, we used resiniferatoxin (RTX) to block the conduction of transient receptor potential vanilloid subtype 1 (TRPV1) positive fibers (mostly C- and Adelta-fibers) and bupivacaine microspheres to block all fibers of the sciatic nerve in rats before spared nerve injury (SNI), and observed spinal microglial changes 2 days later. RESULTS: SNI induced robust mechanical allodynia and p38 activation in spinal microglia. SNI also induced marked cell proliferation in the spinal cord, and all the proliferating cells (BrdU+) were microglia (Iba1+). Bupivacaine induced a complete sensory and motor blockade and also significantly inhibited p38 activation and microglial proliferation in the spinal cord. In contrast, and although it produced an efficient nociceptive block, RTX failed to inhibit p38 activation and microglial proliferation in the spinal cord. CONCLUSION: (1) Blocking peripheral input in TRPV1-positive fibers (presumably C-fibers) is not enough to prevent nerve injury-induced spinal microglial activation. (2) Peripheral input from large myelinated fibers is important for microglial activation. (3) Microglial activation is associated with mechanical allodynia.

Anemia and brain oxygen after severe traumatic brain injury.

PURPOSE: To investigate the relationship between hemoglobin (Hgb) and brain tissue oxygen tension (PbtO(2)) after severe traumatic brain injury (TBI) and to examine its impact on outcome. METHODS: This was a retrospective analysis of a prospective cohort of severe TBI patients whose PbtO(2) was monitored. The relationship between Hgb-categorized into four quartiles (≤9; 9-10; 10.1-11; >11 g/dl)-and PbtO(2) was analyzed using mixed-effects models. Anemia with compromised PbtO(2) was defined as episodes of Hgb ≤ 9 g/dl with simultaneous PbtO(2) < 20 mmHg. Outcome was assessed at 30 days using the Glasgow outcome score (GOS), dichotomized as favorable (GOS 4-5) vs. unfavorable (GOS 1-3). RESULTS: We analyzed 474 simultaneous Hgb and PbtO(2) samples from 80 patients (mean age 44 ± 20 years, median GCS 4 (3-7)). Using Hgb > 11 g/dl as the reference level, and controlling for important physiologic covariates (CPP, PaO(2), PaCO(2)), Hgb ≤ 9 g/dl was the only Hgb level that was associated with lower PbtO(2) (coefficient -6.53 (95 % CI -9.13; -3.94), p < 0.001). Anemia with simultaneous PbtO(2) < 20 mmHg, but not anemia alone, increased the risk of unfavorable outcome (odds ratio 6.24 (95 % CI 1.61; 24.22), p = 0.008), controlling for age, GCS, Marshall CT grade, and APACHE II score. CONCLUSIONS: In this cohort of severe TBI patients whose PbtO(2) was monitored, a Hgb level no greater than 9 g/dl was associated with compromised PbtO(2). Anemia with simultaneous compromised PbtO(2), but not anemia alone, was a risk factor for unfavorable outcome, irrespective of injury severity.

Hand-arm vibration syndrome with proximal ulnar artery occlusion.

The case of a man exposed during 25 years to vibration while maneuvering a heavy earth moving tractor is reported. The first clinical manifestation of hand-arm vibration syndrome was a bilateral Raynaud's phenomenon followed five years later by digital necrosis. The arteriography revealed a proximal and bilateral ulnar artery occlusion. Bilateral median nerve conduction abnormalities were also present. Vibration exposure level was much higher than the threshold level proposed by the European Commission. Laboratory examinations for vasculitis and other vascular diseases were all negative. The purpose of this report is to show that vibration can be responsible for proximal occlusion of a medium sized artery and severe neurovascular abnormalities which must be distinguished from the usual vasospastic Raynaud's phenomenon and the classical hypothenar hammer syndrome. An early and correct diagnosis is crucial because continued repetitive trauma can result in irreversible ischemic injury and loss of digits.