Drugs in fall versus non-fall accidents with major trauma - A population-based clinical and medico-legal autopsy study.

BACKGROUND: The main aim of the present population-based study was to compare drugs in fall versus non-fall accidents causing major trauma, including both clinical and medico-legal autopsy data. METHODS: All individuals with accidents resulting in major trauma, a new injury severity score (NISS)>15 or lethal outcome was identified at hospital and/or the Department of Forensic Medicine between 2011 and 2013. Modified Downton Fall Risk Index ranged from 0 to 7, and was based on specific pharmaceuticals (max 5 points), previous fall (1 point) and cognitive impairment (1 point). RESULTS: One hundred and four individuals with major traumatic accidents were identified, 38 (36.5%) died. The median modified Downton Fall Risk Index was 2 for fall accidents and 0 for non-fall accidents (p < 0.001). Modified Downton Fall Risk Index was an age-independent factor associated with fall accident (p < 0.001). The medico-legal autopsy rate for in-hospital patients was 50% (6/12) for fatal fall accidents in comparison with 92.3% (12/13) for fatal non-fall accidents (p = 0.03). In individuals undergoing medico-legal autopsy, the proportion of individuals with any detected drug was 77% in fall accidents compared to 39% in non-fall accidents (p = 0.036). The presence of sedatives (p = 0.002) and bensodiazepines (p = 0.023) were higher for fall accidents compared to non-fall accidents. CONCLUSION: This population-based study on accidents with major trauma showed that drugs had high impact on fall accidents with major trauma. It seems warranted from a public health perspective to study if implementation of medication review guidelines at hospital managing polypharmacy issues may prevent fall accident recidivism.

Socio-economic status and major trauma in a Scandinavian urban city: A population-based case-control study.

AIMS: Epidemiological studies of patients with major trauma, including both hospitalized and immediately deceased whom are undergoing medico-legal autopsy, are very rare. We studied the incidence and mortality of major trauma in all 10 districts in the Scandinavian city of Malmö, Sweden, and the association between socio-economic status and major trauma. METHODS: Major trauma was defined as a New Injury Severity Score > 15, or a lethal outcome due to trauma. Cases with a registration address in Malmö between 1 January 2011 and 31 December 2013 were identified from the red trauma alarm list in the hospital and the autopsy register in the Forensic Department. Statistics Sweden matched each case with four randomly selected age-, gender- and district-matched controls. Social assistance within the household, level of education, income and capital income were compared. RESULTS: We identified 117 cases (80 men and 37 women) with a median age of 48.0 years (IQR 28.5-65.0). The incidence of major trauma in Malmö was 12.7 (95% CI 10.4-15.0) per 100,000 person-years; and 69 died due to major trauma, with 8.4 (95% CI 6.4-10.4) per 1000 deaths. Lower income (p = 0.024), no income (OR 1.6; 95% CI 1.0-2.4; p = 0.037) and social assistance (OR 2.3; 95% CI 1.3-4.1; p = 0.003) were associated with major trauma. The level of education was not found to be related to major trauma (p = 0.47). CONCLUSIONS: Low income and social assistance within the household were associated with major trauma in the city of Malmö, but not the level of education; in this age-, gender- and district-matched case-control study of major trauma.

Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.

BACKGROUND AND PURPOSE: Cannabidiol has been reported to act as an antagonist at cannabinoid CB1 receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB1 receptors. EXPERIMENTAL APPROACH: Internalization of CB1 receptors, arrestin2 recruitment, and PLCß3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 receptors and in the STHdh(Q7/Q7) cell model of striatal neurons endogenously expressing CB1 receptors. Cells were treated with 2-arachidonylglycerol or Δ(9)-tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol. KEY RESULTS: Cannabidiol reduced the efficacy and potency of 2-arachidonylglycerol and Δ(9)-tetrahydrocannabinol on PLCß3- and ERK1/2-dependent signalling in cells heterologously (HEK 293A) or endogenously (STHdh(Q7/Q7)) expressing CB1 receptors. By reducing arrestin2 recruitment to CB1 receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB1 receptor. CONCLUSIONS AND IMPLICATIONS: Cannabidiol behaved as a non-competitive negative allosteric modulator of CB1 receptors. Allosteric modulation, in conjunction with effects not mediated by CB1 receptors, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.

Necessity of including medico-legal autopsy data in epidemiological surveys of individuals with major trauma.

BACKGROUND: It is rare that epidemiological surveys of patients with major trauma include both those admitted to the emergency department and those sent for medico-legal autopsy. The main aim of the present population-based study of major trauma was to examine the importance of medico-legal autopsy data. METHODS: A new injury severity score (NISS)>15 or lethal outcome was used as criteria for major trauma and to identify patients at the emergency, anaesthesiology and forensic departments and/or being within the jurisdiction of the Malmö police authority and subjected to a medico-legal autopsy between 2011 and 2013. According to Swedish legislation all trauma related deaths should be reported to the police who refer these cases for medico-legal autopsy. RESULTS: Among the 174 individuals included, 92 (53%) died and 81 (47%) underwent medico-legal autopsy. One hundred twenty-six patients were primarily admitted to hospital and 48 died before admission to hospital and were sent directly for medico-legal autopsy. Forty-four in-hospital deaths occurred, of whom 33 (75%) were sent to medico-legal autopsy. In those sent directly to the department of forensic medicine the proportion of accidents was lower (p<0.001), self-inflicted injuries higher (p<0.001) and gunshot wounds higher (p=0.002) in comparison with those sent to hospital. The most prevalent drugs detected by forensic toxicology screening in the 81 fatalities were ethanol (20%), sedatives (16%), anti-depressives (15%) and illicit narcotics (9%). Forty-four cases (54%) were positive for at least one drug, and twenty-eight cases (35%) were positive for two or more drugs. Factors associated with a lower rate of medico-legal autopsies among trauma-related deaths at hospital were high age (p<0.001), lower NISS (p<0.001), a longer duration between trauma and death (p<0.001), falls (p=0.030) and trauma-related infections (p<0.001). CONCLUSION: This population based study covering clinical and forensic data shows that more than half of the individuals sustaining major trauma died. An additional 25% of the in-hospital fatalities should have undergone medico-legal autopsy according to legislation, but did not. The high proportion of positive toxicological findings among fatalities examined at medico-legal autopsy implies that toxicology screening should be routine in major trauma patients, in order to improve treatment and prevention.

Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects.

Hyperglycemic crises of diabetic ketoacidosis and nonketotic hyperglycemia are associated with elevation of counterregulatory hormones and proinflammatory cytokines, markers of lipid peroxidation, and oxidative stress. To investigate if other conditions besides hyperglycemia could evoke such a prompt increase in cytokine levels, lipid peroxidation, and oxidative stress markers, we induced hypoglycemic stress by standard insulin tolerance test and measured proinflammatory cytokines, markers of lipid peroxidation, reactive oxygen species (ROS), and counterregulatory hormones. Insulin tolerance test was performed in 13 healthy male subjects with no history of infection, cardiovascular risk factors, or abnormal glucose. At baseline and at 30, 45, 60, 120, and 240 minutes after insulin injection, the following parameters were measured: glucose, cortisol, corticotropin, epinephrine (EP), norepinephrine (NE), growth hormone, tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, IL-6, IL-8, free fatty acids, white blood cells, lipid peroxidation markers by thiobarbituric acid assay, and ROS by dichlorofluorescein method. The peak value of white blood cell count at 120 minutes was significantly associated with the peak values of NE at 30 minutes and cortisol at 60 minutes. By comparing the area under the curve of measured parameters, EP emerged as significant predictor of TNF-alpha (P = .05) and IL-8 (P = .027). Cortisol emerged as predictor of IL-1beta significantly (P = .05). Corticotropin predicted area under the curve of IL-6 with borderline significance (P = .06). In the present study, insulin-induced hypoglycemia in nondiabetic male subjects is associated with increased proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-8), markers of lipid peroxidation, ROS, and leukocytosis. Elevations of NE, EP, corticotropin, and cortisol in hypoglycaemia are associated with the elevation of the proinflammatory cytokines and leukocytosis.