Diantha B. Howard

Transforming growth factor-beta 1 reduces infarct size after experimental cerebral ischemia in a rabbit model.

Background and Purpose: The aim of this study was to examine the effect of transforming growth factor‐&bgr;1, a cytokine shown to amelioriate cardiac ischemia, in a rabbit model of thromboembolic stroke. Methods: An autologous clot embolus was introduced intracranially through the right internal carotid artery in 21 New Zealand White rabbits, with seven in each group receiving either vehicle control (albumin) or 10 or 50 &mgr;g transforming growth factor‐&bgr;1 administered as an intracarotid bolus immediately before autologous clot embolization. Multiple physiological parameters were monitored, including regional cerebral blood flow, arterial blood gases, hematocrit, glucose, core temperature, and mean arterial pressure. The brain was harvested 4 hours after embolization, and infarct size was determined planimetrically as a percentage of the entire hemisphere. Results: Brain infarct size was reduced in both the 10 ‐ &mgr;g (16.7 ± 4.0% [mean±SEM], p< 0.05) and 50 ‐ &mgr;g (21.7±4.5%) transforming growth factor‐&bgr;1‐treated groups when compared with the control group (31.9±6.6%). Regional cerebral blood flow did not show any significant intergroup or intragroup variation over time, although the 10‐&mgr;g transforming growth factor‐&bgr;1 group experienced a greater return of cerebral blood flow in the first 2 hours after embolization. Conclusions: Transforming growth factor‐&bgr;1 reduced brain infarct size in a rabbit model of thromboembolic stroke. This effect was not related to a direct effect on blood flow. Studies are ongoing to determine the mechanism by which transforming growth factor‐&bgr;1 salvages ischemic brain. (Stroke 1993;24:558‐562)

Neurodevelopmental Outcome of Extremely Low Birth Weight Infants from the Vermont Oxford Network: 1998–2003

Background: Physicians and parents face significant uncertainties when making care decisions for extremely low birth weight (ELBW) infants. Many published estimates of death and developmental outcome are from well-funded university programs and may not reflect outcomes of infants from a variety of settings. The best estimates of the probabilities of death and severe disability combine local experience and published data. Objective: To describe the neurodevelopmental outcome of ELBW infants from centers of the ELBW Infant Follow-Up Group of the Vermont Oxford Network (VON) and to identify characteristics associated with severe disability. Methods: Predefined measures of living situation, health and developmental outcome were collected at 18–24 months’ corrected age for infants born from July 1, 1998 to December 31, 2003 with birth weights of 401–1,000 g at 33 North American VON centers. Logistic regression was used to identify characteristics associated with severe disability. Results: 6,198 ELBW infants were born and survived until hospital discharge; by the time of follow-up, 88 infants (1.4%) had died. Of the remaining 6,110 infants, 3,567 (58.4%) were evaluated. Severe disability occurred in 34% of the assessed infants. Multivariate logistic regression suggested cystic periventricular leukomalacia, congenital malformation and severe intraventricular hemorrhage were the characteristics most highly associated with severe disability. There were marked variations among the follow-up clinics in the attrition rate. Conclusion: ELBW infants completing evaluation were at a high risk for severe disability. There are considerable differences among participating centers in attrition at follow-up. Further resources will be needed to study the effect of follow-up care for this group of infants.

Increased reactivity of platelets induced by fibrinogen independent of its binding to the IIb-IIIa surface glycoprotein:: a potential contributor to cardiovascular risk

OBJECTIVES To determine whether augmented activation (degranulation) of platelets might contribute to the association between higher concentrations of fibrinogen and risk of myocardial infarction, we characterized adenosine diphosphate (ADP)-induced expression of P-selectin by platelets in whole blood as a function of this exposure to selected concentrations of fibrinogen. BACKGROUND An increased risk of myocardial infarction has been associated with increased concentrations of fibrinogen. METHODS Fibrinogen was added to blood anticoagulated with corn trypsin inhibitor (a specific inhibitor of Factor XIIa without effect on other coagulation factors). Degranulation of platelets was identified by flow cytometry. RESULTS Addition of fibrinogen to blood did not activate platelets under basal conditions (without ADP). By contrast, a concentration-dependent increase in ADP and thrombin receptor agonist peptide (TRAP)-induced activation occurred with increasing concentrations of fibrinogen. Increased ADP-induced degranulation was apparent with the addition of 100 mg/dl of fibrinogen (p < or = 0.001 for 1.5 micromol/liter ADP, n=10 subjects). Inhibition by abciximab of binding of fibrinogen to the surface glycoprotein IIb-IIIa did not attenuate the observed augmentation of reactivity induced by fibrinogen. Augmented degranulation was associated with uptake of fibrinogen into alpha-granules without surface binding despite pretreatment with abciximab as shown by laser scanning confocal microscopy. CONCLUSIONS Fibrinogen in blood augments degranulation of platelets in response to ADP and is accompanied by uptake of fibrinogen into alpha-granules. Thus, elevated concentrations of fibrinogen secondary to inflammation implicated in cardiovascular risk may operate, in part, by increasing reactivity of platelets.

Differences between Activation Thresholds for Platelet P-Selectin and Glycoprotein IIb-IIIa Expression and Their Clinical Implications

Increased platelet reactivity is a descriptor of the risk of cardiovascular events in healthy men and in patients with overt coronary artery disease. We sought to determine if differential thresholds exist for activation of platelets with respect to alpha-granule degranulation and fibrinogen binding in healthy volunteers and in patients with acute coronary syndromes. We also sought to characterize the effect of aspirin on activation. Platelet activation was assessed with flow cytometry in whole blood anticoagulated with corn trypsin inhibitor and incubated with fluorescein isothiocyanate conjugated fibrinogen (to define activation of glycoprotein IIb-IIIa), a phycoerythrin conjugated antibody to P-selectin (a marker of alpha-granule degranulation), and selected concentrations of adenosine diphosphate (ADP) or thrombin receptor agonist peptide. ADP-induced fibrinogen binding was found to be a low threshold activation event (40% of platelets bound fibrinogen in response to 0.2 microM ADP). Alpha-granule degranulation was a higher threshold event (33% of platelets expressed P-selectin in response to 1.0 microM ADP). Intra- and interindividual variability were most apparent with low concentrations of agonist (0.2 microM ADP). Patients with acute coronary syndromes (on aspirin) had significantly increased P-selectin expression in response to ADP compared with healthy subjects (on aspirin), but no difference in ADP-induced fibrinogen binding was observed. Daily ingestion of 325 mg of aspirin had no effect on either P-selectin expression or fibrinogen binding in healthy subjects. Analysis of platelet reactivity with flow cytometry characterizes activation with respect to specific components of the process and should facilitate development and optimal titration of antiplatelet therapy.

Intrapartum and Postpartum Analgesia for Women Maintained on Methadone During Pregnancy

OBJECTIVE: To determine whether methadone maintenance alters intrapartum or postpartum pain or medication requirements. METHODS: Sixty-eight patients treated with methadone for opiate dependence during pregnancy (vaginal n=35; cesarean n=33) were matched retrospectively to control women. Analgesic medication and pain scores (0–10) were extracted from the medical record. The primary endpoint was opiate use postpartum (oxycodone equivalents). The secondary endpoints were pain scores and intrapartum analgesia. RESULTS: There were no differences in intrapartum pain or analgesia. After vaginal birth, methadone-maintained women experienced increased pain (methadone, 2.7 [1.9–5.0]; control, 1.4 [0.5–3.0], P=.001) but no increase in opiate use ([mean±standard deviation] methadone 12.7±32.1; control 6.8±12.7 mg/24 h, P=.33); after cesarean delivery both pain (methadone, 5.3 [4.1–6.0]; control, 3.0 [2.2–3.9], P=.001) and opiate use (methadone, 91.6±51.8; control, 54.0±18.6 mg/24 h, P=.001) increased. CONCLUSION: Methadone-maintained women have similar analgesic needs and response during labor, but require 70% more opiate analgesic after cesarean delivery. LEVEL OF EVIDENCE: II

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study

Objective: To characterize patients misdiagnosed with multiple sclerosis (MS). Methods: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. Results: Of 110 misdiagnosed patients, 51 (46%) were classified as “definite” and 59 (54%) “probable” misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. Conclusions: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

Intrapartum and postpartum analgesia for women maintained on buprenorphine during pregnancy

Objective: To determine whether buprenorphine maintenance alters intrapartum or postpartum pain or medication requirements.

Complement depletion does not reduce brain injury in a rabbit model of thromboembolic stroke

The contribution of the complement system to cerebral ischemic and ischemia/reperfusion injury was examined in a rabbit model of thromboembolic stroke by delivery of an autologous clot embolus to the intracranial circulation via the internal carotid artery. A two-by-two factorial design was employed to study the impact of complement depletion via pretreatment with cobra venom factor (CVF, 100 U/kg i.v.) in the setting of permanent (without tissue plasminogen activator; t-PA) and transient (with t-PA) cerebral ischemia. Thirty-two New Zealand white rabbits were assigned to one of four groups (n=8, each group): control without t-PA, control with t-PA, CVF without t-PA and CVF with t-PA. In the complement intact animals, t-PA administration resulted in an approximate 30% reduction in infarct size when compared to the group not receiving t-PA (20.4+/-6.6% of hemisphere area vs. 30.1+/-7.2%; mean+/-SEM). However, infarct sizes in the complement depleted rabbits, with (30.7+/-8.2%) or without (30.2+/-7.9%) t-PA, were no different from the control group receiving no therapy. Similarly, no difference in regional cerebral blood flow or final intracranial pressure values was noted between any of the four groups. Complement activation does not appear to be a primary contributor to brain injury in acute thromboembolic stroke.

NEUTROPHIL ACTIVATION IN ACUTE HUMAN CENTRAL NERVOUS SYSTEM INJURY

The hypothesis that neutrophil activation exacerbates brain injury in acute stroke is currently receiving wide acceptance. However, the temporal relationship of neutrophil activation to the ischemic event in clinical states is not clear. Therefore, this study was undertaken to examine human neutrophil activation by the technique of luminol-dependent chemiluminescence in both acute bland and hemorrhagic stroke. Patients (bland, n = 18; hemorrhagic, n = 16) were entered into this study within six hours of the ictus. These results were compared to other clinical central nervous system insults: subarachnoid hemorrhage (n = 11), spinal trauma (n = 9) and isolated closed head injury (n = 19). All subjects were sampled upon presentation to the emergency room and 0.5, 1, 2, 3, 4 and 5 days following the event. Neutrophil activation, as determined by luminol-dependent chemiluminescence, was evident at day 1 following the ictus in the bland stroke group (p < 0.05), although this trend was not demonstrated for hemorrhagic stroke. Patients suffering a closed head injury demonstrated greater initial neutrophil activation with values being significantly lower than baseline at days 0.5 (p = 0.01) and 1 (p = 0.05). No significant change was demonstrated for the groups with spinal trauma or subarachnoid hemorrhage. These results support a role for neutrophil activation during various central nervous system insults and provide a temporal framework for considering drug therapy directed at transient suppression of neutrophil function.

Neurodevelopmental Outcome of Infants Resuscitated with Air or 100% Oxygen: A Systematic Review and Meta-Analysis

Background: The use of air for the initial resuscitation of newborn infants has been shown to reduce neonatal mortality. However, a precise estimate of the neurodevelopmental status upon follow-up of infants resuscitated in air is lacking. Objective: To perform a meta-analysis of all studies reporting resuscitation of newborn infants with air or 100% oxygen that included follow-up data. Methods: Bibliographic databases were searched. In addition, we estimated the effect of loss to follow-up on our analysis of abnormal neurodevelopmental outcome. Results: We identified 10 studies in which newborn infants had been randomly or quasi-randomly assigned to resuscitation with air or 100% oxygen. Three of these 10 studies had available follow-up data. A total of 678 infants were enrolled at centers that performed follow-up of these infants. Of these, 113 died, leaving 565 infants potentially eligible for follow-up. A total of 414 children were evaluated (73% of eligible children; 195 resuscitated with air and 219 with 100% oxygen). In the air group, 12.8% of infants had an abnormal neurodevelopmental outcome, compared with 10.5% in the 100% oxygen group [typical relative risk (RR) 1.24, 95% confidence interval 0.73–2.10]. This is consistent with an RR of abnormal development as low as 0.41 or as high as 2.28. Conclusions: Long-term follow-up did not detect any significant differences in these two groups regarding abnormal development. However, the results are imprecise and could be consistent with significant harm or benefit.