During programmed cell death, activation of caspase-3 leads to proteolysis of DNA repair proteins, cytoskeletal proteins, and the inhibitor of caspase-activated deoxyribonuclease, culminating in morphologic changes and DNA damage defining apoptosis. The participation of caspase-3 activation in the evolution of neuronal death after traumatic brain injury in rats was examined. Cleavage of pro-caspase-3 in cytosolic cellular fractions and an increase in caspase-3-like enzyme activity were seen in injured brain versus control. Cleavage of the caspase-3 substrates DNA-dependent protein kinase and inhibitor of caspase-activated deoxyribonuclease and co-localization of cytosolic caspase-3 in neurons with evidence of DNA fragmentation were also identified.

The influence of anesthetic agents on cerebral blood flow (CBF) was tested in normal rats. CBF is quantified with arterial spinlabeled MRI in rats anesthetized with either an opiate (fentanyl), a potent inhalation anesthetic agent (isoflurane), or a barbiturate (pentobarbital) using doses commonly employed in experimental paradigms. CBF values were found to be about 2. Despite the frequent use of anesthetics in experimental MRI in rats using techniques such as arterial spin labeling (ASL) and blood oxygenation level-dependent (BOLD) signal changes, quantitative assessment of the effect of commonly used anesthetics on cerebral blood flow (CBF) in these protocols is limited (1). Assessment of the effect on CBF of fentanyl, a potent narcotic analgesic agent frequently administered in the clinical neuroanesthesia and neurointensive care setting, is limited even using conventional techniques applied to normal rats (2,3). To this end, we quantified CBF using the continuous ASL method (CASL) in rats administered fentanyl (10 g kg Ϫ1 bolus, then 50 g kg Ϫ1 h Ϫ1 intravenously (IV), during ventilation with N 2 O/O 2 , 2:1) and compared these findings to those observed using isoflurane (1% by inhalation in N 2 O/O 2 , 1:1) or pentobarbital (50 mg kg Ϫ1 h Ϫ1 IV, during ventilation with N 2 /O 2 , 1:1) anesthetic regimens. METHODS Animal ModelThe study protocol was approved by the University of Pittsburgh Animal Care and Use Committee. Twelve mature male Sprague-Dawley rats (332-390 g) were anesthetized with isoflurane and N 2 O/O 2 , 1:1, endotracheally intubated and mechanically ventilated. A femoral arterial catheter and a double lumen venous catheter were surgically inserted for blood sampling, for pressure monitoring, and for administration of agents. Rats were assigned to one of three anesthetic groups for CBF measurements: fentanyl, isoflurane, or pentobarbital (n ϭ 4 per group). Isoflurane was then continued at 1% by inhalation (isoflurane group), or discontinued and either fentanyl (10 g kg Ϫ1 bolus, then 50 g kg Ϫ1 h Ϫ1) or pentobarbital (50 mg kg Ϫ1 h Ϫ1 ) was administered IV. N 2 O/O 2 was continued in fentanyl (2:1) and isoflurane (1:1) groups. Rats were ventilated with N 2 /O 2 , 1:1 in the pentobarbital group. Fentanyl or isoflurane anesthesia was administered with N 2 O because this approach is frequently used in clinical neuroanesthesia (4) and in experimental models (5,6). Similarly, to mirror clinical (7) and laboratory (8) usage, pentobarbital was administered without N 2 O. In the pentobarbital group, N 2 O was replaced with N 2 to match the fraction of inspired oxygen concentration in the isoflurane-anesthetized group. After a 30-min equilibration period, perfusion images were acquired in duplicate. In all studies pancuronium bromide (0.1 mg kg Ϫ1 h Ϫ1) was administered IV for paralysis. Rectal temperature was continually monitored and maintained at 37°C with a heated water blanket. Arterial blood gases and mean arterial blood pressure (MABP) were also monitored throughout the NMR studies. Respiratory t...

Poly(ADP-ribose) polymerase-1 (PARP-1) is a homeostatic enzyme that paradoxically contributes to disturbances in spatial memory acquisition after traumatic brain injury (TBI) in transgenic mice, thought to be related to depletion of its substrate nicotinamide adenine dinucleotide (NAD + ). In this study, systemic administration of the PARP-1 inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP) after TBI preserved brain NAD + levels and dose-dependently reduced poly-ADPribosylation 24 h after injury. While moderate-dose INH2BP improved spatial memory acquisition after TBI; strikingly, both injured-and sham-mice receiving high-dose INH2BP were unable to learn in the Morris-water maze. Poly-ADP-ribosylated peptides identified using a proteomics approach yielded several proteins potentially associated with memory, including structural proteins (tubulin a and b, c-actin, and a-internexin neuronal intermediate filament protein) and 14-3-3c. Nuclear poly-ADP-ribosylation of 14-3-3c was completely inhibited by the dose of INH2BP that produced profound memory disturbances. Thus, partial inhibition of poly-ADP-ribosylation preserves NAD + and improves functional outcome after TBI, whereas more complete inhibition impairs spatial memory acquisition independent of injury, and is associated with ribosylation of 14-3-3c. Keywords: 14-3-3, DNA damage, head injury, 5-iodo-6-amino-1,2-benzopyrone, nicotinamide adenine dinucleotide, poly(ADP-ribose) synthetase. Poly(ADP-ribose) polymerase-1 (PARP-1; E.C.2.4.2.30) is an abundant nuclear protein that is activated by single-strand DNA breaks, produced by a variety of insults including reactive oxygen and nitrogen species, chemical agents, and UV irradiation (Dawson and Dawson 1995;Szabo 1996). Activated PARP-1 utilizes nicotinamide adenine dinucleotide (NAD + ) as a substrate for generating large branching adenosine diphosphate (ADP)-ribose polymers on various proteins including histones, topoisomerases, and PARP-1 itself (Szabo 1998). PARP-1 activation facilitates DNA repair by enabling other enzymes to locate and replace missing base pairs (Szabo et al. 1997;Bauer et al. 2000). Neuronal death and neurologic dysfunction after CNS injury appears to be mediated in part by activation of PARP-1, particularly CNS insults associated with DNA damage and energy failure such as cerebral ischemia (Eliasson et al. 1997;Endres et al. 1998a) and traumatic brain injury (TBI;Whalen et al. 1999;LaPlaca et al. 2001). While disruption of the PARP-1 gene Received December 17, 2002; revised manuscript received January 14, 2003; accepted January 15, 2003. Address correspondence and reprint requests to Robert S. B. Clark, Safar Center for Resuscitation Research, 3434 Fifth Avenue, Pittsburgh, PA 15260, USA. E-mail: clarkrs@ccm.upmc.edu Abbreviations used: 2-AB, 3-aminobenzamide; ADP, adenosine diphosphate; CCI, controlled cortical impact; DMSO, dimethyl sulphoxide; DTT, dithiothreitol; Hsc54, heat shock cognate protein 54; IEF, isoelectric focusing; INH2BP, 5-iodo-6-amino-1,2-benzopyrone; IPG, i...

This study examines the impact of OSHA inspections on injuries in manufacturing plants. The authors use the same model and some of the same plant-level data employed by several earlier studies that found large effects of OSHA inspections on injuries for 1979-85. These new estimates indicate that an OSHA inspection imposing a penalty reduced lost-workday injuries by about 19% in 1979-85, but that this effect fell to 11% in 1987-91, and to a statistically insignificant 1% in 1992-98. The authors cannot fully explain this overall decline, which they find for nearly all subgroups they examine-by inspection type, establishment size, and industry, for example. Among other findings are that, across the years studied, inspections with penalties were more effective than those without, and the effects on injury rates were greater in smaller plants and nonunion plants than in large plants and union plants. SinceCongress's establishment of the Occupational Safety and Health Administration (OSHA) in 1970 to prevent occupational injuries and illnesses, there has been considerable debate over the program's effectiveness.Each year, OSHA conducts tens of thousands of inspections and imposes millions of dollars in penalties, but most workplaces are only rarely visited, penalties are low relative to the cost of abating many workplace hazards, and many injuries are unrelated to OSHA standards.Many empirical studies examining OSHA have been done, using both industry-level and plant-level data.

We examined the Occupational Safety and Health Administration's (OSHA) inspections in the US to identify the effects of repeated inspections and the time between inspections on noncompliance. Our sample included 549,398 inspections conducted from 1972 through 2006 in manufacturing plants in the 29 states where federal OSHA enforces the law. We controlled for inspection type, industry, establishment size, and year. The number of total violations cited fell by 28%-48% from the first to the second inspection; after that, the numbers declined much more slowly. These effects were found in every one of the four sub-periods examined. The number of violations cited increased with each additional year since the prior inspection after controlling for other variables; however, the increases were small, totaling approximately 15% over five years. OSHA should probably give higher priority to first time inspections than to repeated inspections. The current requirement that at least two years elapse between planned inspections should probably be lengthened. important for OSHA and others concerned with workplace safety to learn about the effectiveness of the enforcement program and how to improve it. This is especially true because, over the years, OSHA (perhaps more than any other regulatory agency in the US) has been criticized for being both ineffective and meddlesome.In this article, we focus on how non-compliance with OSHA standards changes as an establishment undergoes repeated inspections and what the implications are for regulatory enforcement. Ideally, of course, the focus should be on the impact of these activities on the reduction of injuries and illnesses, not simply on compliance. In the language of program evaluation, citing violations is an "activity," abating hazards is an "output," but the desired outcome is the prevention of injuries, illnesses, and the resulting losses. We return to this topic in the Conclusion and Implication sections. For now, we simply note that there appears to be a positive, if weak, correlation between injuries per 100 workers and violations per 100 workers; and, more importantly, there is evidence that compliance with at least some standards does prevent injuries Haviland et al. 2010).The literature on regulatory enforcement draws on, among other things, the economic model of deterrence. In that model, the regulated actors make decisions based on the expected costs and benefits of compliance. Enforcement programs can increase the costs of non-compliance, where the expected cost is a function of the probability of detection and the penalty once detected. When the regulated actors are businesses, few doubt that economic incentives can influence behavior, although the magnitude of the impact that any given incentive will generate is usually unclear.Our focus in this article is on "specific deterrence," a term that refers to the effects on behavior of actually being inspected or subjected to sanctions for non-compliance. "General deterrence" refers to the impact on behavior of the perceived...

We examine different models of employers' responses to OSHA inspections. The "detection/correction" model assumes that responses are limited to correcting the violations that inspectors cite. The "behavioral shock" model assumes that firms respond by paying more attention to safety issues, even those unrelated to OSHA standards. We test whether some injury types are more affected by inspections than others, or by citations of particular OSHA standards. We conclude that, although citing particular standards can reduce injury types specifically related to those hazards, inspections also affect a wider range of injuries, suggesting a broader impact on managerial attention to safety.

New TRISS and ASCOT coefficients should be derived if survival for patients with blunt injuries is to be predicted accurately in independent trauma registries. Also, it may be wise to consider developing separate models for subgroups of patients, particularly if hospitals in the registry have different mixes of patient types.

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