Attention-deficit/hyperactivity disorder genomics: update for clinicians.

Attention deficit, hyperactivity disorder (ADHD) is familial and highly heritable. Several candidate genes involved in neurotransmission have been identified, however these confer minimal risk, suggesting that for the most part, ADHD is not caused by single common genetic variants. Advances in genotyping enabling investigation at the level of the genome have led to the discovery of rare structural variants suggesting that ADHD is a genomic disorder, with potentially thousands of variants, and common neuronal pathways disrupted by numerous rare variants resulting in similar ADHD phenotypes. Heritability studies in humans also indicate the importance of epigenetic factors, and animal studies are deciphering some of the processes that confer risk during gestation and throughout the post-natal period. These and future discoveries will lead to improved diagnosis, individualized treatment, cures, and prevention. These advances also highlight ethical and legal issues requiring management and interpretation of genetic data and ensuring privacy and protection from misuse.

Fasciotomy worsens the amount of myonecrosis in a porcine model of crotaline envenomation.

STUDY OBJECTIVE: We evaluate the efficacy of fasciotomy or crotaline snake antivenom in reducing myonecrosis. METHODS: We used a randomized, blinded, controlled acute animal preparation. Twenty anesthetized swine were injected intramuscularly in the anterior tibiales muscle of both hind limbs with 6 mg/kg of Crotalus atrox venom (total of 12 mg/kg of venom per animal). Immediately after venom injection, the right hind limb underwent fasciotomy. Muscle biopsies were obtained from the fasciotomized hind limb at 0, 4, and 8 hours and from the other hind limb at the conclusion of the study (8 hours). In addition, animals received either 8 vials of reconstituted Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) or an equal volume of normal saline solution intravenously 1 hour after venom injection. A pathologist blinded to the study determined the percentage of myonecrotic cells in each biopsy. Statistical analysis was performed using repeated measures analysis of variance for compartment pressure. Rank-order methods were used for comparison of myonecrosis between groups. RESULTS: Biopsies from hind limbs undergoing fasciotomy revealed a progressive increase in the amount of myonecrosis over time (myonecrosis median at 0, 4, or 8 hours [or death]: 0%, 14%, or 14.5%, respectively; P<.001). Comparison of the amount of myonecrosis of biopsies at death or 8 hours revealed that limbs that underwent fasciotomy had significantly more myonecrosis than those that did not (myonecrosis median: 14.5% versus 2.5%, P=.048). No difference was detected in the amount of myonecrosis when FabAV was compared with normal saline solution on final biopsies from either fasciotomy or nonfasciotomy hind limb (myonecrosis median: 10.0% versus 10.0%, P=.64). CONCLUSION: Fasciotomy significantly worsens the amount of myonecrosis in a porcine model of intramuscular crotaline venom injection. No change in the amount of myonecrosis was detected with the use of FabAV treatment at the dosages used in this animal model.

Crotalidae polyvalent immune Fab antivenom limits the decrease in perfusion pressure of the anterior leg compartment in a porcine crotaline envenomation model.

STUDY OBJECTIVE: Crotalidae Polyvalent Immune Fab (CroFab; FabAV) antivenom prevents a decrease in perfusion pressures in intramuscular crotaline envenomation compared with normal saline solution. METHODS: We used a randomized, blinded, controlled acute animal preparation. Twenty anesthetized and instrumented swine were injected intramuscularly with 6 mg/kg Crotalus atrox venom into the anterior tibialis muscle of each hind limb (time 0). One hour after envenomation (time 1 hour), animals were randomized to receive 8 vials of reconstituted FabAV or an equal volume of normal saline solution (control) through a central venous line. The main outcome variable was the area under the perfusion-time curve (AUC) of the anterior compartment of the hind limb measured from time 1 hour to time 8 hours. Perfusion pressure was defined as mean arterial pressure-compartment pressure. Additionally, physiologic variables, including pulse rate, prothrombin time, fibrinogen level, platelet count, hemoglobin level, and hematocrit level, were monitored. RESULTS: Venom injection resulted in a decrease in average perfusion pressures from 54.1 mm Hg (time 0) to 31.7 mm Hg (time 1 hour). Comparison of AUC between groups from time 1 hour (time of treatment) to the completion of the study at time 8 hours revealed a 57% greater AUC in animals that received FabAV (mean+/-SD: 211.1+/-67.9 versus 134.5+/-55.8 mm Hg/h; P =.036; 95% confidence interval for difference 5.9 to 147.3). Comparison of the time curves for the mean prothrombin time from time 1 hour to the completion of the study by means of repeated-measures analysis of variance revealed a significant increase in the control group (P =.02). No significant difference was detected in the time curves for the means of mean arterial pressure, compartment pressure, pulse rate, hemoglobin level, hematocrit level, fibrinogen level, or platelet count over the course of the study. FabAV was found to significantly increase survival time when compared with the effect of the normal saline solution control from time 1 hour to time 8 hours, as determined by means of Kaplan-Meier estimation and the log-rank test (P =.029). CONCLUSION: FabAV limits the decrease in perfusion pressures in the anterior leg compartment after intramuscular crotaline venom injection in swine compared with saline solution. In addition, FabAV might prevent the development of coagulopathy and increase survival time in this model.