Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in ...CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol‐O‐methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.
To report the results of contralateral recession-resection of the horizontal muscles in oculomotor nerve palsy with aberrant regeneration to correct both the strabismus and the ptosis in one ...procedure.
Retrospective case series.
This is an institutional study on patients with oculomotor nerve palsy with aberrant innervation who had contralateral eye muscle surgery in 2 different centers. Patients were included if they have both exotropia and aberrant regeneration with a ptosis that improved on adduction. All patients had contralateral lateral rectus recession and medial rectus resection. Ductions, versions, angle of misalignment, and degree of ptosis were evaluated before surgery and at last follow-up.
Eleven patients were identified. The mean age at surgery was 15.0 ± 9.2 years. Five patients were male (45%). Trauma was the cause in 8 (72%) cases. The mean angle of exotropia was 42 ± 14 prism diopters. The mean degree of ptosis was 3.9 ± 1.6 mm. The mean lateral rectus recession was 8.2 ± 1.1 mm, and the mean medial rectus muscle resection was 6.7 ± 0.9 mm. The mean follow-up was 6.4 ± 2.5 months. After surgery, none of the patients had residual exotropia >10 prism diopters. The mean degree of ptosis after surgery was 0.9 ± 0.8 mm. None of the patients required further surgery for ptosis or strabismus.
Contralateral eye muscle in third nerve palsy with aberrant innervation offers the advantage of simultaneous correction of both strabismus and ptosis through a single procedure.
•Contralateral surgery can be done in third nerve palsy with aberrant innervation.•This allows simultaneous correction of both the exotropia and ptosis in one step.•Contralateral surgery avoids the complications related to ptosis surgery.
Systemic inflammatory reactions have been postulated to exacerbate neurodegenerative diseases via microglial activation. We now demonstrate in vivo that repeated systemic challenge of mice over four ...consecutive days with bacterial LPS maintained an elevated microglial inflammatory phenotype and induced loss of dopaminergic neurons in the substantia nigra. The same total cumulative LPS dose given within a single application did not induce neurodegeneration. Whole-genome transcriptome analysis of the brain demonstrated that repeated systemic LPS application induced an activation pattern involving the classical complement system and its associated phagosome pathway. Loss of dopaminergic neurons induced by repeated systemic LPS application was rescued in complement C3-deficient mice, confirming the involvement of the complement system in neurodegeneration. Our data demonstrate that a phagosomal inflammatory response of microglia is leading to complement-mediated loss of dopaminergic neurons.
The occurrence of a hydrogen‐bonded contact ion pair (HBCIP, in the gas phase) between the dibenzotropylium cation and chloride has been suggested previously. However, the low barrier (ΔE‡, of ~1 ...kcal/mol) to its covalent counterpart can preclude its detection. In this work it is shown (through density functional theory calculations) that ΔE‡ can be increased significantly, based on larger but similar carbocations containing more benzene rings. Using the electrostatic potential as a measure of carbocation stability, along with its linear correlation with ΔE‡, one obtains a ΔE‡ value as high as ~3.7 kcal/mol for the HBCIP between the heptabenzotropylium cation and chloride. The trend for ΔE‡ can be explained by the deformation energy of the carbocation, from its structure in the HBCIP to that in the transition state.
Increasing the kinetic stability of metastable species is a key feature to its detection. This work shows how this stability of some hydrogen‐bonded contact ion‐pairs (HBCIP) can be increased, increasing the size of the aromatic carbocation which it contains.
Valproic acid (VPA) has been reported to inhibit cancer cell growth and has therapeutic use in retinal diseases. However, the mechanism of this action remains unclear. In order to explore this ...mechanism, primary human retinal pigment epithelial (hRPE) cell cultures were established. Cell viability was assessed by the trypan blue exclusion method (T), and the cell proliferation was measured by
H-thymidine incorporation (3H-thy). P38 synthesis was quantitated by using 14C-methionine-labeled P38 (14C-P38) by using P38-specific antibody. SB203580 (SB), a selective inhibitor of p38 MAPK, was also used to test the specificity of P38 stimulation. Antinuclear staining (NS) studies were performed by DAPI. Statistical significance was established by student's t-test. We observed that VPA (1 mM) inhibited 10% fetal bovine serum (FBS)-stimulated cell proliferation (1.75 ± 0.37 vs. 3.25 ± 0.68 cells per 1 μl ± SEM, p < 0.05, n = 4). VPA also stimulated 14C-P38 synthesis in a dose-dependent manner. SB (30 μM) inhibited VPA (4 mM)-stimulated 14C-P38 synthesis (197.74 ± 41.17 vs. 425.89 ± 59.17, CPM ± SEM, p < 0.05, n = 4) and increased hRPE cell proliferation (1.79 ± 0.45 vs. 4.93 ± 1.12 cells per 1 μl ± SEM, p < 0.05, n = 4); NS demonstrated VPA-induced cell damage. We conclude that VPA inhibits hRPE cell growth via P38 MAP mechanism and may be of therapeutic value in treating or preventing proliferative eye diseases.
War at the Speed of Light describes the revolutionary and
ever-increasing role of directed-energy weapons (such as laser,
microwave, electromagnetic pulse, and cyberspace weapons) in
warfare. Louis ...A. Del Monte delineates the threat that such weapons
pose to disrupting the doctrine of Mutually Assured Destruction,
which has kept the major powers of the world from engaging in
nuclear warfare. Potential U.S. adversaries, such as China and
Russia, are developing hypersonic missiles and using swarming
tactics as a means to defeat the U.S. military. In response, the
U.S. Department of Defense established the 2018 National Security
Strategy, emphasizing directed-energy weapons, which project
devastation at the speed of light and are capable of destroying
hypersonic missiles and enemy drones and missile swarms. Del Monte
analyzes how modern warfare is changing in three fundamental ways:
the pace of war is quickening, the rate at which weapons project
devastation is reaching the speed of light, and cyberspace is now
officially a battlefield. In this acceleration of combat called
"hyperwar," Del Monte shows how disturbingly close the world is to
losing any deterrence to nuclear warfare.
Study objective Δ-9-Tetrahydrocannabinol homologs have been increasingly abused since their introduction in 2004. Such products were used as a “legal high” for those wishing to experience cannabinoid ...effects while evading basic drugs-of-abuse testing. We describe a series of exposures to products marketed as synthetic cannabinoids to better characterize the clinical effects in these patients. Methods All Δ-9-tetrahydrocannabinol homolog exposures reported to the National Poison Data System between January 1, 2010, and October 1, 2010, were extracted with National Poison Data System generic codes and product codes for Δ-9-tetrahydrocannabinol homologs. Only cases involving a single-agent exposure to Δ-9-tetrahydrocannabinol homologs as the major category were analyzed. Descriptive statistics were generated for demographic data, management site, products involved, symptoms, duration of effects, treatments, and severity of clinical effects. Results During the 9-month study period, there were 1,898 exposures to Δ-9-tetrahydrocannabinol homologs; 1,353 of these cases were single-agent exposures. The mean age was 22.5 years (SD 8.86 years). Most cases were reported in men (n=1,005; 74.3%). The majority of exposures were acute (88.2%; n=1,193). The most common clinical effect was tachycardia (37.7%; n=510). Seizures were reported in 52 patients (3.8%). The majority of clinical effects lasted for fewer than 8 hours (n=711; 78.4%) and resulted in 1,011 non–life-threatening clinical effects (92.9%). The most common therapeutic intervention was intravenous fluids (n=343; 25.3%). There was 1 death (0.1%). Conclusion The majority of cases were in young men intentionally abusing spice. Most exposures resulted in non–life-threatening effects not requiring treatment, although a minority of exposures resulted in more severe effects, including seizures.
To review the prevalence of preoperative and postoperative intorsion in patients with strabismus and Graves' eye disease (GED), and to correlate the intorsion with coexisting superior rectus (SR) and ...superior oblique (SO) muscle enlargement as a possible mechanism causing intorsion in these patients.
Charts of consecutive patients with GED who underwent strabismus surgery between 1 January 2010 and 1 April 2013 were retrospectively reviewed. Of these, patients with orbital CT or MRI scan were identified for further analysis. Clinical characteristics documented included age, gender, horizontal and vertical deviation, subjective torsional deviation, specific extraocular muscles (EOMs) operated upon, EOM enlargement on CT/MRI scans and width and thickness of SO, SR group and inferior rectus (IR).
Charts of 45 patients (14 males and 31 females) were reviewed. Mean age was 56.8±12.5 years. Of these, seven (15.6%) patients demonstrated intorsion, and 38 (84.4%) patients demonstrated extorsion preoperatively. But after strabismus surgery, 15 (39.5%) of the 38 patients with preoperative extorsion demonstrated postoperative intorsion and 23 (60.5%) patients continued to show postoperative extorsion. On analysis of CT/MRI scans in these patients, only an increase in the thickness of SR group and the thickness/width of SO muscle were significantly associated with preoperative and postoperative intorsion; while age, gender, preoperative horizontal or vertical deviation and IR recession were unrelated to preoperative or postoperative intorsion. Postoperative intorsion was also associated with smaller degrees of preoperative extorsion (<3.5°).
Preoperative SR and/or SO muscle enlargement appear to be a primary contributing factor relating to preoperative and postoperative intorsion in patients with GED-associated strabismus. Patients with only small amounts of preoperative extorsion (<3.5°) in the presence of tight IRs should be carefully evaluated for possible SR and/or SO involvement by CT or MRI scan to predict those at risk for and plan for prevention/treatment of postoperative intorsion.
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