Suicide attempts and overdoses among adults entering addictions treatment: comparing correlates in a U.S. National Study.

BACKGROUND: Suicide attempts and non-fatal overdoses are both associated with substance use. The aim of the present study was to examine correlates of suicide attempts and non-fatal overdoses simultaneously among individuals seeking addictions treatment. METHODS: A large U.S. national sample of individuals entering addictions treatment participated in a cross-sectional survey (n=5892). Multinomial logistic regression modeling tested the adjusted associations of violence, injection drug use, specific substances, and depressive symptoms with a four-category outcome variable based on prior histories of suicide attempt and non-fatal overdose (neither, suicide attempt only, overdose only, both), adjusting for demographic and treatment characteristics. RESULTS: Sexual and physical victimization was associated with suicide attempts with or without overdoses (ORs 1.25-2.84), while perpetrating violence was associated with having experienced either or both outcomes (ORs 1.25-1.56). Depressive symptoms had a stronger association with suicide attempts (OR=3.05) than overdoses (OR=1.29). Injection drug use was associated with overdoses with or without suicide attempts (ORs 2.65-3.22). Individuals seeking treatment for marijuana use were less likely have overdosed or attempted suicide (ORs 0.39-0.67), while individuals seeking treatment for heroin use were more likely to have overdosed (OR=1.46). Seeking treatment for use of more than one substance was associated with overdose and overdose and suicide attempt (ORs 1.58-2.51), but not suicide attempt alone. CONCLUSIONS: The present findings indicate that suicide and overdose are connected yet distinct problems. Individuals who have had a history of both may be a group with particularly poor psychological functioning as well as more severe drug-related problems.

Optic nerve damage in shaken baby syndrome: detection by beta-amyloid precursor protein immunohistochemistry.

BACKGROUND: Rapid acceleration-deceleration of an infant's head during intentional shaking should in theory exert stretch or shear forces upon the optic nerves sufficient to cause axonal injury. beta-Amyloid precursor protein (beta-APP) immunohistochemistry recently has been shown to be a highly effective method for identifying diffuse axonal injury in the brains of infants with shaken baby syndrome. In this study, we investigated the utility of beta-APP in identifying optic nerve damage in infants who have sustained fatal whiplash shaking. MATERIALS AND METHODS: beta-Amyloid precursor protein immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of eyes (including optic disc and distal optic nerve) from infants less than 1 year of age with shaken baby syndrome (5 cases), combined shaken baby syndrome/blunt head trauma (3 cases), and "pure" blunt head trauma (1 case). Nontraumatic control cases included infants who died of suffocation (1 case), sudden infant death syndrome (1 case), and positional asphyxia (1 case) and an enucleation from a child with a retinoblastoma (1 case). Matched hematoxylin-eosin-and neurofilament-stained sections were used for comparison. RESULTS: Three of the 5 shaken baby cases and all 3 combined shaken baby/blunt head trauma cases had optic nerve axonal injury identified by the presence of strongly beta-APP-immunoreactive beaded or swollen axonal segments. Axonal injury could not be detected in the corresponding hematoxylin-eosin-or neurofilament-stained sections. Optic nerve axonal injury was not seen in the case involving pure blunt head trauma or in the nontraumatic control cases. CONCLUSIONS: Optic nerve axonal injury is a prominent feature of intentional fatal whiplash head trauma in infants less than 1 year of age. beta-Amyloid protein precursor immunohistochemistry appears to be the most effective method for demonstrating axonal damage in the optic nerve.

Infant rat model of the shaken baby syndrome: preliminary characterization and evidence for the role of free radicals in cortical hemorrhaging and progressive neuronal degeneration.

Infants subjected to repeated episodes of violent shaking develop brain damage characterized by intracranial hemorrhage and progressive cortical atrophy. We have developed an animal model that mimics this pathological state and investigated its etiology and treatment. Anesthetized male rats, 6 days of age, were subjected to one episode of shaking per day for 3 consecutive days. Separate groups of rats were sacrificed 1 h postinjury on the third day of shaking for HPLC quantification of cortical .OH and vitamin E levels, and histological assessment of cortical hemorrhaging. Additional groups were sacrificed 7 or 14 days postinjury to demonstrate progressive neuronal degeneration via cortical wet weight comparisons. In comparison to noninjured shams, the results indicated that cortical vitamin E and .OH levels rose 53.7% (p < 0.005) and 457.1% (p < 0.001), respectively, in shaken infant rats. Brain histologies revealed a moderate-to-severe degree of cortical hemorrhaging in these animals 1 h postinjury. By 7 and 14 days postinjury, there was a 13.3% and 28.7% (p < 0.0001 vs. sham) loss of cortical tissue in shaken infants, respectively, indicating progressive neuronal degeneration. Treatment with 10 mg/kg (ip) of the 21-aminosteroid antioxidant, tirilazad mesylate, 10 min before and 2 h after each episode of shaking, resulted in a 53.1% attenuation of cortical .OH levels and a 34.9% decrease in brain hemorrhaging (p < 0.05 vs. vehicle). Tirilazad treatment did not, however, significantly effect cortical vitamin E concentrations at 1 h postinjury or the extent of progressive neuronal degeneration at either 7 or 14 days postinjury. The present animal model mimics the brain pathology seen in abused children. Our observation that tirilazad mesylate, an antioxidant-lipid peroxidation inhibitor, significantly reduces cortical .OH levels and brain hemorrhaging in shaken infant rats supports a role for oxygen radicals in the pathophysiology of this type of CNS injury. The failure of tirilazad to block progressive cortical degeneration suggests that mechanisms other than free radicals may be of prime importance in the mediation of this aspect of the pathology.

Tirilazad widens the therapeutic window for riluzole-induced attenuation of progressive cortical degeneration in an infant rat model of the shaken baby syndrome.

Our infant rat model of traumatic subarchnoid hemorrhage combines violent shaking and hypoxia to produce subdural hemorrhaging and progressive cortical degeneration similar to that seen in victims of the shaken baby syndrome. Anesthetized, 6-day-old male rats were subjected to one episode of shaking under hypoxic conditions. Brain histologies revealed moderate-to-severe cortical hemorrhaging at 48 h postinjury and progressive cortical degeneration, as indicated by a 15.3% and 20.2% reduction in cortical wet weight, at 7 and 14 days postinjury, respectively. The purpose of the present study was to assess the effects of two antioxidant lipid peroxidation inhibitors (tirilazad mesylate and PNU-101033E), and the glutamate release inhibitor (riluzole), upon the brain pathology seen in this model. A significant, 54.3-75.3%, reduction in cortical hemorrhaging was observed in rats that were treated with a total of three doses of tirilazad (10 mg/kg, i.p.): 10 min before or 5-30 min after injury, and again at 2 and 24 h postinjury (p < 0.01 vs. vehicle). However, treatment with tirilazad or the more potent, brain-penetrating pyrrolopyrimidine, PNU-101033E (10 min before plus 2, 24, 48, and 72 h after), did not attenuate the progressive cortical degeneration typically seen at 14 days postinjury. These results suggest that free radicals play an important role in the pathophysiology of secondary brain hemorrhaging due to shaking + hypoxia, but may not be critical in the mediation of the subsequent neurodegeneration. Rather, glutamate neurotoxicity may be a key factor here. This is suggested by our observation that the glutamate release inhibitor, riluzole, significantly reduced cortical degeneration when it was administered up to 1 h postinjury in the present model. Specifically, the cortical wet weights of rats treated with 8 mg/kg riluzole (i.p.) 10 min before or 1 h after shaking + hypoxia (and again at 24 h postinjury) were 95.3% and 97.4% of noninjured controls, respectively, at 14 days postinjury (p < 0.02 vs. vehicle). Riluzole treatment beyond 1 h (e.g., 2 or 4 h postinjury) did not reduce the neurodegeneration. Lastly, we attempted to demonstrate that the therapeutic window for riluzole-induced attenuation of cortical degeneration could be extended beyond 1 h through the use of combination therapy. In this experiment, rat pups were treated with 10 mg/kg tirilazad (i.p.) at 30 min postinjury followed by 8 mg/kg riluzole (i.p.) at 4 and 24 h postinjury. At 14 days postinjury, the cortical wet weights of these rats were 94.5% of noninjured controls, thus demonstrating significant neuroprotection (p < 0.05 vs. vehicle) and a widening of the therapeutic window from 1 to 4 h in length. These results suggest that early attenuation of free radical-induced lipid peroxidation may slow down the biochemical cascade of events related to glutamate-induced excitotoxicity and, in doing so, prolong the time during which a glutamate release inhibitor, such as riluzole, is effective.