Thirteen Cases of Valeryl Fentanyl in Michigan: A Call for Expanding Opioid Testing.

ABSTRACT: In this report, we describe 13 cases of drug overdose in Michigan in which valeryl fentanyl was found in postmortem blood. Valeryl fentanyl is a schedule I opioid that is rarely found in drug overdoses in the United States. Although little data exist on the mortality and morbidity associated with valeryl fentanyl, its molecular structure indicates that it would be less potent than fentanyl.When analyzing blood samples for valeryl fentanyl, samples from peripheral sites were sometimes negative for quantitative levels; however, samples from central sites in the same decedent were positive. This could indicate unique pharmacokinetics for valeryl fentanyl, which could have implications for other fentanyl analogs. Given the paucity of pharmacodynamic information, the prohibition of its use, the potential to buttress law enforcement efforts in monitoring drug trafficking trends, and to determine the efficacy of current regulations, laboratories should test for valeryl fentanyl. When testing for valeryl fentanyl, and likely other fentanyl analogs, the site of sample collection is important: central sources of blood are preferred to peripheral sources.

Phase-function normalization for accurate analysis of ultrafast collimated radiative transfer.

The scattering of radiation from collimated irradiation is accurately treated via normalization of phase function. This approach is applicable to any numerical method with directional discretization. In this study it is applied to the transient discrete-ordinates method for ultrafast collimated radiative transfer analysis in turbid media. A technique recently developed by the authors, which conserves a phase-function asymmetry factor as well as scattered energy for the Henyey-Greenstein phase function in steady-state diffuse radiative transfer analysis, is applied to the general Legendre scattering phase function in ultrafast collimated radiative transfer. Heat flux profiles in a model tissue cylinder are generated for various phase functions and compared to those generated when normalization of the collimated phase function is neglected. Energy deposition in the medium is also investigated. Lack of conservation of scattered energy and the asymmetry factor for the collimated scattering phase function causes overpredictions in both heat flux and energy deposition for highly anisotropic scattering media. In addition, a discussion is presented to clarify the time-dependent formulation of divergence of radiative heat flux.

Self-neglect: adaptation of a clinical tool to the practice of the medical examiner.

Self-neglect is the inability or unwillingness to provide for oneself the goods and services needed to live safely and independently. It is the most common allegation reported to Adult Protective Services agencies throughout the United States. Unfortunately, it seems that most medical examiners and their teams are not trained appropriately on self-neglect and forget to ask pertinent questions and document relevant observations. The most important aspect of self-neglect for the medical examiner is to recognize the diagnosis to avoid confusion with other forms of elder abuse, particularly neglect from a third party. In this context, a self-neglect scale could be a useful tool to assist the death investigation team. In the clinical field, a self-neglect severity scale was developed by the Consortium for Research in Elder Self-Neglect of Texas. It is here proposed that a self-neglect severity scale for medical examiners should be developed, to assist the investigative team in assessing these common cases. This scale is developed by modifying the clinical scale to adapt it to the particular needs of death investigation. This scale can help the medical examiner and his team in approaching these deaths in a systematic and comprehensive way.

PREPARED: Comparison of prolonged and immediate release ropinirole in advanced Parkinson's disease.

BACKGROUND: PREPARED was a randomized, parallel-group, double-blind, multicenter study to evaluate the efficacy of adjunctive ropinirole prolonged release (PR) versus immediate release (IR) in patients with advanced Parkinson's disease (PD). METHODS: Patients received once-daily PR (2-24 mg/d; n = 177) or three-times-daily IR (0.75-24 mg/d; n = 173) for 24 weeks. The primary endpoint was the proportion of patients maintaining ≥ 20% reduction from baseline in "off" time over two consecutive visits at Week 24 last observation carried forward (LOCF). RESULTS: At Week 24 LOCF, PR significantly increased the proportion of patients maintaining ≥ 20% reduction in "off" time versus IR (adjusted odds ratio: 1.82; 95% CI: 1.16, 2.86; P = 0.009). Mean (SD) doses at Week 24 LOCF were: PR, 18.6 (6.5) mg/d; IR, 10.4 (6.4) mg/d; mean (SD) reductions from baseline in levodopa (L-dopa) dose were -162 (226) mg and -113 (138) mg, respectively. Adverse events (AEs) were reported by 72% of patients in the PR group and 61% in the IR group; 12% and 9% of patients, respectively, withdrew from the study due to an AE, and 6% and 5%, respectively, reported serious AEs. CONCLUSIONS: Adjunctive PR provided a significantly greater improvement in symptom control in terms of the odds of achieving ≥ 20% maintained reduction in time spent "off" compared with IR. Interpretation may be confounded by the higher doses of PR versus IR that were achieved, in combination with lower doses of L-dopa by the study end. Despite dosing differences, the PR titration regimen was generally well tolerated, with an AE profile similar to that of IR.

Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3.

Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury through activation of its receptor, Toll-like receptor 4 (TLR4). Paradoxically, TLR activation by endogenous ligands after ischemia worsens stroke damage. Here, we define a novel, protective role for TLRs after ischemia in the context of LPS preconditioning. Microarray analysis of brains collected 24 h after stroke revealed a unique set of upregulated genes in LPS-pretreated animals. Promoter analysis of the unique gene set identified an overrepresentation of type I interferon (IFN)-associated transcriptional regulatory elements. This finding suggested the presence of type I IFNs or interferon regulatory factors (IRFs), which upregulate interferon-stimulated genes. Upregulation of IFNbeta was confirmed by real-time reverse transcription-PCR. Direct administration of IFNbeta intracerebroventricularly at the time of stroke was sufficient for neuroprotection. TLR4 can induce both IFNbeta and interferon-stimulated genes through its adapter molecule Toll/interleukin receptor domain-containing adaptor-inducing IFNbeta (TRIF) and the IRF3 transcription factor. We show in oxygen glucose deprivation of cortical neurons, an in vitro model of stroke, that activation of TRIF after stroke reduces neuronal death. Furthermore, mice lacking IRF3 were not protected by LPS preconditioning in our in vivo model. Our studies constitute the first demonstration of the neuroprotective capacity of TRIF/IRF3 signaling and suggest that interferon-stimulated genes, whether induced by IFNbeta or by enhanced TLR signaling to IRF3, are a potent means of protecting the brain against ischemic damage.

Inflammation and the emerging role of the toll-like receptor system in acute brain ischemia.

BACKGROUND AND PURPOSE: Systemic administration of cytosine-guanine (CpG) oligodeoxynucleotides provides neuroprotection against subsequent cerebral ischemic injury. We examined the genomic response of leukocytes and brain cells after ischemia in the context of CpG preconditioning. METHODS: RNA was isolated from circulating leukocytes and ischemic cortex 3 and 24 hours after middle cerebral artery occlusion after CpG or saline pretreatment and subjected to microarray analysis. Genes uniquely upregulated in CpG-pretreated mice were examined for overrepresented transcriptional regulatory elements. RESULTS: CpG preconditioning induced a novel response to middle cerebral artery occlusion within circulating leukocytes that was dominated by natural killer cell-associated genes and the GATA-3 transcriptional regulatory element. Preconditioning also caused a novel brain response to stroke that was dominated by Type I interferon, interferon-associated genes, and transcriptional regulatory elements. CONCLUSIONS: CpG preconditioning invokes novel leukocyte and brain responses to stroke. In this, CpG may be a unique preconditioning agent, coordinating peripheral and brain responses to protect against ischemic injury.

Rap1-mediated activation of extracellular signal-regulated kinases by cyclic AMP is dependent on the mode of Rap1 activation.

Like other small G proteins of the Ras superfamily, Rap1 is activated by distinct guanine nucleotide exchange factors (GEFs) in response to different signals to elicit cellular responses. Activation of Rap1 by cyclic AMP (cAMP) can occur via cAMP-dependent protein kinase A (PKA)-independent and PKA-dependent mechanisms. PKA-independent activation of Rap1 by cAMP is mediated by direct binding of cAMP to Rap1-guanine nucleotide exchange factors (Rap1-GEFs) Epac1 (exchange protein directly activated by cAMP 1) and Epac2 (Epac1 and Epac2 are also called cAMP-GEFI and -GEFII). The availability of cAMP analogues that selectively activate Epacs, but not PKA, provides a specific tool to activate Rap1. It has been argued that the inability of these analogues to regulate extracellular signal-regulated kinases (ERKs) signaling despite activating Rap1 provides evidence that Rap1 is incapable of regulating ERKs. We confirm that the PKA-independent activation of Rap1 by Epac1 activates a perinuclear pool of Rap1 and that this does not result in ERK activation. However, we demonstrate that this inability to regulate ERKs is not a property of Rap1 but is rather a property of Epacs themselves. The addition of a membrane-targeting motif to Epac1 (Epac-CAAX) relocalizes Epac1 from its normal perinuclear locale to the plasma membrane. In this new locale it is capable of activating ERKs in a Rap1- and cAMP-dependent manner. Rap1 activation by Epac-CAAX, but not wild-type Epac, triggers its association with B-Raf. Therefore, we propose that its intracellular localization prevents Epac1 from activating ERKs. C3G (Crk SH3 domain Guanine nucleotide exchanger) is a Rap1 exchanger that is targeted to the plasma membrane upon activation. We show that C3G can be localized to the plasma membrane by cAMP/PKA, as can Rap1 when activated by cAMP/PKA. Using a small interfering RNA approach, we demonstrate that C3G is required for the activation of ERKs and Rap1 by cAMP/PKA. This activation requires the GTP-dependent association of Rap1 with B-Raf. These data demonstrate that B-Raf is a physiological target of Rap1, but its utilization as a Rap1 effector is GEF specific. We propose a model that specific GEFs activate distinct pools of Rap1 that are differentially coupled to downstream effectors.

A Comparison of Venous versus Capillary Blood Samples when Measuring Blood Glucose Using a Point-of-Care, Capillary-Based Glucometer.

BACKGROUND: Blood glucose level (BGL) is routinely assessed by paramedics in the out-of-hospital setting. Most commonly, BGL is measured using a blood sample of capillary origin analyzed by a hand-held, point-of-care glucometer. In some clinical circumstances, the capillary sample may be replaced by blood of venous origin. Given most point-of-care glucometers are engineered to analyze capillary blood samples, the use of venous blood instead of capillary may lead to inaccurate or misleading measurements. HYPOTHESIS/PROBLEM: The aim of this prospective study was to compare mean difference in BGL between venous and capillary blood from healthy volunteers when measured using a capillary-based, hand-held, point-of-care glucometer. METHODS: Using a prospective observational comparison design, 36 healthy participants provided paired samples of blood, one venous and the other capillary, taken near simultaneously. The BGL values were similar between the two groups. The capillary group had a range of 4.3mmol/l, with the lowest value being 4.4mmol/l and 8.7mmol/l the highest. The venous group had a range of 2.7mmol/l, with the lowest value being 4.1mmol/l and 7.0mmol/l the highest.For the primary research question, the mean BGL for the venous sample group was 5.3mmol/l (SD = 0.6), compared to 5.6mmol/l (SD = 0.8) for the capillary group. This represented a statistically significant difference of 0.3mmol/l (P = .04), but it did not reach the a priori established point of clinical significance (1.0mmol/l). Pearson's correlation coefficient for capillary versus venous indicated moderate correlation (r = 0.42). CONCLUSION: In healthy, non-fasted people in a non-clinical setting, a statistically significant, but not clinically significant, difference was found between venous- and capillary-derived BGL when measured using a point-of-care, capillary-based glucometer. Correlation between the two was moderate. In this context, using venous samples in a capillary-based glucometer is reasonable providing the venous sample can be gathered without exposure of the clinician to risk of needle-stick injury. In clinical settings where physiological derangement or acute illness is present, capillary sampling would remain the optimal approach.

Role of silicon contamination on calcification of hydrophilic acrylic intraocular lenses.

PURPOSE: To verify the presence of the element silicon on hydrophilic acrylic intraocular lenses (IOLs) explanted because of calcification. DESIGN: Interventional case series with clinicopathological correlation. METHODS: Twenty explanted IOLs with surface deposits (MemoryLens), and 20 with deposits mostly within their optic substance (SC60B-OUV and Aqua-Sense; 10 each) were used. After gross, microscopic, and histochemical analyses to confirm the presence of deposits, the lenses underwent scanning electron microscopy (SEM) with energy dispersive x-ray spectroscopy (EDS) for elemental composition, on the external surface of MemoryLens IOLs, and on the surface and internal substance of SC60B-OUV and Aqua-Sense IOLs. The weight percentage of the element silicon was obtained at the level of deposits, and at adjacent deposit-free areas in all lenses. RESULTS: Scanning electron microscopy (SEM) coupled with EDS confirmed that the composition of the deposits was calcium/phosphate in all cases. The element silicon was found in all 40 lenses, on all areas analyzed. The silicon weight percentage was higher at the level of the deposits. The presence of aluminum on five MemoryLens IOLs, and in most of the SC60B-OUV and Aqua-Sense lenses might be related to scattering from the aluminum mounting stubs used for surface analyses. CONCLUSIONS: Silicone compounds have been implicated in the calcification of another hydrophilic acrylic design (Hydroview). They may also have a role in the calcification of other hydrophilic acrylic IOLs. Further investigation on the relationship between the presence of the element silicon and the silicone compounds found on calcified hydrophilic acrylic lenses is necessary.

Acute effect of vasectomy on the function of the rat epididymal epithelium and vas deferens.

Persistent infertility after apparently successful vasectomy reversal is common. One possible etiology is epididymal epithelial dysfunction resulting in improper sperm maturation after vasectomy reversal. The epididymal epithelium secretes a number of proteins that are thought to be required for the maturation of sperm. Ligation of the vas deferens during vasectomy may affect the synthesis of some of these proteins. In the present study, the function of the epididymal epithelium was assessed at early times after vasectomy (1, 4, and 7 days) by measuring the level of mRNA of 4 secreted proteins: Crisp-1, clusterin, osteopontin, and transferrin. In addition, the site of synthesis of these proteins was determined by immunocytochemistry. The results demonstrated that the expression of Crisp-1 and clusterin, representative epididymal secretory proteins, was largely unaffected by vasectomy. However, osteopontin mRNA increased in the vas deferens in response to vasectomy. Immunocytochemical localization of osteopontin suggested that both infiltrating immune cells and deferential luminal epithelium were responsible for this up-regulation. Transferrin expression was viewed as a marker for immune cells at the site of injury. However, both the caput epididymis and deferential epithelia were found to express transferrin, in addition to immune cells. In conclusion, there appear to be only minor changes in expression of genes encoding epididymal secretory proteins acutely after vasectomy, but, not surprisingly, there was evidence of an inflammatory response after vasectomy.

New photochromic foldable intraocular lens: preliminary study of feasibility and biocompatibility.

PURPOSE: To evaluate a new hydrophobic acrylic intraocular lens (IOL) with photochromic properties in vitro and in vivo in a rabbit model. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. METHODS: The photochromic optic change of 5 study IOLs was evaluated in vitro on ultraviolet (UV) light exposure. The tests were done in the dry state and during immersion of the lenses in a balanced salt solution. Six additional IOLs were implanted in the right eye of New Zealand rabbits. The left eyes were implanted with SA60AT or SN60AT IOLs (Alcon Laboratories, 3 each). After a clinical follow-up of 6 months, the rabbits were killed and their eyes enucleated. Three study IOLs and 2 control SN60AT IOLs were evaluated in vitro on UV exposure after explantation. The other IOLs and the rabbit eyes had histopathologic examination. RESULTS: On in vitro UV light exposure, the optic of the study IOLs changed from colorless to yellow, turning again colorless on discontinuation of UV light projection. The same photochromic change was also observed on UV light exposure throughout the clinical follow-up of 6 rabbits, as well as after explantation of the IOLs. Postoperative clinical inflammatory reactions and cellular reactions on the surface of the explanted IOLs were similar in the study and control groups. No sign of untoward toxicity was observed in the histopathological sections of the rabbit eyes in all groups. CONCLUSIONS: The new photochromic IOL turned yellow only on exposure to UV light; otherwise it remained clear. This lens was also found to be biocompatible.

Interlenticular opacification: dual-optic versus piggyback intraocular lenses.

PURPOSE: To evaluate and compare the incidence of capsular bag opacification, particularly interlenticular opacification (ILO), in rabbit eyes implanted with a dual-optic silicone intraocular lens (IOL) or piggyback lenses. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. METHODS: Ten dual-optic study IOLs (Synchrony), 10 control pairs of piggyback silicone-plate lenses, and 10 control pairs of piggyback single-piece hydrophobic acrylic lenses were implanted in the capsular bag of 30 rabbit eyes following phacoemulsification. After a 6-week follow-up, the rabbits were killed and their eyes enucleated. Anterior capsule opacification and posterior capsule opacification were graded on a 0 to 4 scale from a posterior or Miyake-Apple view. Interlenticular opacification was noted in relation to the center of the interlenticular space (periphery, paracentral, and central area) and to the number of quadrants involved. The eyes were then evaluated histopathologically. RESULTS: Postoperative inflammatory reaction was similar in all groups. Interlenticular opacification formation was statistically different among the 3 groups of lenses (ILO extension, P = .0013, and ILO extension x ILO quadrants, P = .0023; Kruskal-Wallis test). Pairwise post comparisons of ILO formation showed that the differences between the study IOL group and the silicone-plate lens group were not significant. Interlenticular opacification post comparisons between the hydrophobic acrylic lenses and the study lens or the silicone-plate lenses were significant (P = .002 and P = .001, respectively). Histopathologic examination showed extension of the proliferating cortical material from the peripheral Soemmering's ring into the interlenticular space, causing ILO, especially with the pairs of hydrophobic acrylic lenses. CONCLUSIONS: In this rabbit model, ILO was significantly associated with pairs of hydrophobic acrylic lenses implanted in the bag. This study appears to confirm clinical observations that implantation of 2 silicone-plate lenses in the bag is not associated with ILO. There was also a relative lack of ILO with the dual-optic silicone lens.

Hydrophilic acrylic intraocular lens as a drug-delivery system: Pilot study.

PURPOSE: To evaluate the ability of a hydrophilic acrylic intraocular lens (IOL) to serve as a drug-delivery system for commercially available gatifloxacin and moxifloxacin. SETTING: David J. Apple, MD, Laboratories for Ophthalmic Devices Research, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. METHODS: Hydrophilic acrylic IOLs (C-flex, Rayner Ltd.), presoaked for 24 hours in commercially available solutions of gatifloxacin (Zymar) or moxifloxacin (Vigamox), were implanted in the capsular bag of 6 rabbits for a total of 12 eyes (6 in each group). Aqueous humor samples were taken 2, 4, and 6 hours after implantation. One rabbit served as a control and had nonpresoaked C-flex IOLs implanted. At the end of the operation, 1 drop of Vigamox was applied to the right eye and 1 drop of Zymar was applied to the left eye of the control rabbit. RESULTS: High concentrations of both antibiotics were found in all the samples of the eyes implanted with the presoaked IOLs. The concentrations of the antibiotics decreased over time, but even the 6-hour sample concentrations were markedly higher than the concentrations found in the control rabbit after 4 hours. CONCLUSION: The results suggest that the Rayner C-flex IOL can be effective as a drug-delivery system for fourth-generation fluoroquinolones.

Hydrophilic acrylic intraocular lens as a drug-delivery system for fourth-generation fluoroquinolones.

PURPOSE: To evaluate the ability and safety of a hydrophilic acrylic intraocular lens (IOL) as a drug-delivery system for commercially available gatifloxacin and moxifloxacin. SETTING: David J. Apple, MD, Laboratories for Ophthalmic Research, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, USA. METHODS: Thirty rabbits were divided into 2 similar groups. In Group A (15 rabbits, 30 eyes), hydrophilic acrylic IOLs (C-flex, Rayner Intraocular Lenses, Ltd.) presoaked for 24 hours in commercially available solutions of gatifloxacin 3 mg/mL or moxifloxacin 5 mg/mL were implanted after evacuation of the crystalline lens. Group B (15 rabbits, 30 eyes) had topical preoperative and postoperative cataract prophylaxis with gatifloxacin 3 mg/mL or moxifloxacin 5 mg/mL; IOLs that were not presoaked were also implanted after evacuation of the crystalline lenses. In both groups, aqueous humor samples were taken 4, 8, or 12 hours after IOL implantation (5 eyes at each time point) to determine the antibiotic concentrations. Clinical examinations were performed 24 hours postoperatively. RESULTS: The antibiotic concentrations in Group A (presoaked IOLs) were statistically significantly higher than those in Group B (topical) for both antibiotics in all postoperative samples except moxifloxacin at 12 hours. In both groups, there was no statistically significant difference between the concentrations of the 2 antibiotics. No eye showed signs of clinical toxicity. CONCLUSION: Results show the C-flex IOL is a safe and effective drug-delivery system for fourth-generation fluoroquinolones.

Elemental Characterization and Discrimination of Nontoxic Ammunition Using Scanning Electron Microscopy with Energy Dispersive X-Ray Analysis and Principal Components Analysis.

Concerns over the toxic by-products produced by traditional ammunition have led to an increase in popularity of nontoxic ammunition. In this work, the chemical composition of six brands of nontoxic ammunition was investigated and compared to that of a road flare, which served as an environmental source with similar composition. Five rounds of each brand were fired while a further five were disassembled and the primer alone was fired. Particles collected from all samples, including the road flare, were analyzed by scanning electron microscopy with energy dispersive X-ray analysis. Common elements among the different ammunition brands included aluminum, potassium, silicon, calcium, and strontium. Spectra were then subjected to principal components analysis in which association of the primer to the intact ammunition sample was generally possible, with distinction among brands and from the road flare sample. Further, PCA loadings plots indicated the elements responsible for the association and discrimination observed.

Safety and Efficacy of Siponimod (BAF312) in Patients With Relapsing-Remitting Multiple Sclerosis: Dose-Blinded, Randomized Extension of the Phase 2 BOLD Study.

IMPORTANCE: This dose-blinded extension of the phase 2 BOLD (BAF312 on MRI Lesion Given Once Daily) Study in relapsing-remitting multiple sclerosis provides evidence on disease activity and safety of a range of siponimod doses for up to 24 months. OBJECTIVE: To assess the safety and efficacy of siponimod for up to 24 months during the dose-blinded extension of the BOLD Study. DESIGN, SETTING, AND PARTICIPANTS: At extension baseline in a randomized clinical trial, patients taking siponimod continued at the originally assigned dose and patients taking placebo were rerandomized to the 5 siponimod doses. Initial treatment was titrated over 10 days. A total of 252 eligible patients were treated at specialized multiple sclerosis centers for this study conducted from August 30, 2010, through June 3, 2013. INTERVENTIONS: Siponimod at 10-mg, 2-mg, 1.25-mg, 0.5-mg, and 0.25-mg doses. MAIN OUTCOMES AND MEASURES: Safety assessment included blood tests, documentation of adverse events at regular scheduled visits and Holter monitoring; key efficacy measures were annualized relapse rate and magnetic resonance imaging lesion activity. RESULTS: Among the 252 eligible patients, the mean (SD) ages were 37.2 (8.4) years, 35.2 (9.1) years, 34.0 (7.6) years, 35.1 (9.2) years, and 36.8 (9.1) years in the 0.25-mg, 0.5-mg, 1.25-mg, 2-mg, and 10-mg groups. Of the 252 patients, 184 (73%) entered the extension and received siponimod (10 mg: n = 33; 2 mg: n = 29; 1.25 mg: n = 43; 0.5 mg: n = 29; and 0.25 mg: n = 50); 159 (86.4%) completed the dose-blinded extension. The incidence of adverse events was similar across treatment groups (10 mg: 87.9%; 2 mg: 89.7%; 1.25 mg: 88.4%; 0.5 mg: 96.6%; and 0.25 mg: 84.0%). Nine patients reported serious adverse events (2 mg: 3/29 [10.3%], 1.25 mg: 1/43 [2.3%], 0.5 mg: 4/29 [13.8%], and 0.25 mg: 1/50 [2.0%]; no serious adverse event was reported for more than 1 patient and no new safety signals occurred compared with the BOLD Study. Dose titration mitigated symptomatic bradycardic events. Reductions in mean (95% CI) gadolinium-enhancing T1 lesion counts from the last BOLD assessment were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups (0 [0-0], 0.1 [0-1.9], 0.1 [0-2.6], and 0.1 [0-2.8] at month 24, respectively). At the 3 highest vs 2 lowest doses, the estimated new/newly enlarging T2 lesion counts (95% CIs) were lower during months 6 to 12 (0.5 [0.2-1.3], 0.4 [0.2-1.1], and 0.2 [0.1-0.6] vs 1.3 [0.6-2.8] and 1.4 [0.7-2.7]), months 12 to 18 (0.4 [0.1-1.1], 0.4 [0.1-1.3], and 0.4 [0.2-1.0] vs 1.0 [0.4-2.6] and 3.6 [1.7-7.6]), and months 18 to 24 (0 [0-not estimable], 0.9 [0.1-7.6], and 0.1 [0-1.7] vs 1.6 [0.3-7.7] and 2.0 [0.4-9.5]). Annualized relapse rates (95% CIs) up to month 24 were similarly lower for the 3 highest doses: 0.22 (0.12-0.40) for 10 mg, 0.20 (0.10-0.38) for 2 mg, and 0.14 (0.08-0.26) for 1.25 mg vs 0.33 (0.19-0.56) for 0.5 mg and 0.33 (0.21-0.50) for 0.25 mg. CONCLUSIONS AND RELEVANCE: For up to 24 months of siponimod treatment, multiple sclerosis disease activity was low and there were no new safety signals; investigation in phase 3 trials is encouraged. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01185821.

Postoperative localized opacification of the new MemoryLens design: analyses of an explant.

We describe a different form of opacification of the new MemoryLens intraocular lens model CV232, leading to a decrease in visual acuity and requiring explantation. A well-circumscribed, centrally/paracentrally located opacification of the optic was observed, with the aspect of a small "lens inside the lens." Histochemical and surface analyses revealed the presence of calcified deposits within a void in the optic substance. This void was seen as a linear optic breach in analysis of an optic cylindrical block cut through the area of opacification, from a sagittal view. The origins of the optic void are unclear.

Use of tissue ultrafiltration for treatment of compartment syndrome: a pilot study using porcine hindlimbs.

OBJECTIVES: To demonstrate the efficacy of compartment syndrome ultrafiltration for the treatment of acute compartment syndrome in an animal model. Our hypothesis is the removal of interstitial fluid will result in a reduction of intramuscular pressure compared with untreated controls in a model of bilateral induced compartment syndrome. DESIGN: Controlled experimental model. SETTING: Animal research facility. PATIENTS/PARTICIPANTS: Three pairs of porcine hindlimbs. INTERVENTION: Acute compartment syndrome was created in the pig hindlimb by infusion of saline to maintain the intramuscular pressure 30 mm Hg greater than the animal's mean arterial pressure for 8 hours. After a 2-hour reperfusion interval, ultrafiltration (removal of fluid through 1 mm diameter porous catheters, connected to -500 mm Hg suction) was commenced in 1 limb only and continued for 9.5 hours. MAIN OUTCOME MEASURES: Intramuscular pressure, ultrafiltrate volume, ultrafiltrate and serum levels of creatine kinase and lactate dehydrogenase, histologic measurement of extracellular and intracellular edema, as well as the degree of cellular necrosis. RESULTS: Intramuscular pressure tended to be lower on the treated side at the end of the treatment period [treated leg: 9.3 +/- 4.0 mm Hg (+/- SE), control leg: 19.3 +/- 1.4 mm Hg, P = 0.03]. Analysis of ultrafiltrate fluid showed that levels of creatine kinase and lactate dehydrogenase were elevated compared with serum levels. Creatine kinase levels in serum were measured at 4150 +/- 780 U/L, whereas ultrafiltrate levels of creatine kinase were 28,700 +/- 17,700 U/L (+/- SE) (P = 0.1). Lactate dehydrogenase was measured at 1950 +/- 180 U/L in serum, but markedly elevated in ultrafiltrate [160,000 +/- 88,900 U/L (+/- SE), P = 0.05]. Quantification of cellular and interstitial dimensions showed no difference in control and experimental limbs. Quantification of the degree of muscle necrosis revealed 6.1 +/- 2.7% necrosis in the treated limb compared to 11.3 +/- 1.6% necrosis in the control group (P = 0.02, df = 2, 1-tailed paired t test). CONCLUSION: This pilot study demonstrates the feasibility of tissue ultrafiltration for reduction of intramuscular pressure in this porcine model. Further studies are underway. Compartment syndrome ultrafiltration may be useful prophylactically in patients at risk for acute compartment syndrome. Sampling of interstitial fluid and frequent measurement of intramuscular pressure may allow earlier diagnosis and treatment of acute compartment syndrome, whereas the reduction of tissue pressure by compartment syndrome ultrafiltration may prevent acute compartment syndrome from occurring. Additionally, compartment syndrome ultrafiltration will not hinder the ability of clinicians to use the clinical examination and pressure monitoring as the gold standard.

Predictors of response to pharmacotherapy in social anxiety disorder: an analysis of 3 placebo-controlled paroxetine trials.

BACKGROUND: There is increasing evidence that patients with social anxiety disorder (social phobia) respond to treatment with selective serotonin reuptake inhibitors (SSRIs). Response rates to SSRIs in social anxiety disorder have ranged from at least 50% in controlled trials to up to 80% in open trials. To date, however, there has been little information available about predictors of response to treatment in this disorder. METHOD: Data from 3 placebo-controlled multicenter trials of paroxetine in DSM-IV social anxiety disorder (N = 829) were analyzed using logistic regression to determine predictors of response. Demographic (age, sex), physiologic (baseline heart rate, baseline mean arterial pressure), clinical (baseline social anxiety symptom severity, baseline disability, duration of illness), and trial variables (paroxetine dose, treatment duration) were included. RESULTS: Only duration of treatment was a statistically significant predictor of treatment response. Further analysis demonstrated that, in paroxetine-treated patients in particular, many nonresponders at week 8 (46/166; 27.7%) were responders at week 12. CONCLUSION: These data demonstrate that paroxetine is a reasonable choice of treatment in a broad spectrum of patients with social anxiety disorder. An optimal trial of medication should continue beyond 8 weeks.

Three 18-Electron Tantalum(I) Compounds, TaCl(CO)(2)(dppe)(2), [TaCl(CO)(2)(dppe)(2)](2x), and TaCl(CO)(4)(dppe) (dppe = 1,2-Bis(diphenylphosphino)ethane), Which Exhibit Low Levels of Paramagnetism.

Reductive carbonylation of TaCl(5) in the presence of 1,2-bis(diphenylphosphino)ethane (dppe) under the appropriate conditions results in the formation of TaCl(CO)(2)(dppe)(2) (1), as the major product, and the possibly cyclic oligomer [TaCl(CO)(2)(dppe)(2)](2)(x)() (2, 2x >/= 4) as a minor product. Carbonylation of 1 (1 atm) results in the rapid but reversible formation of TaCl(CO)(4)(dppe) (3). Solutions of all three compounds exhibit low levels of paramagnetism, possibly attributable to thermal population of low-lying triplet excited states. Crystal data for the toluene solvate of 1, C(68)H(64)ClO(2)P(4)Ta: triclinic, P&onemacr; (No. 2), a = 13.937(12) Å, b = 14.811(7) Å, c = 14.929(9) Å, alpha = 102.30(5) degrees, beta = 95.60(7) degrees, gamma = 98.41(5) degrees, Z = 2.