Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study.

Asymmetric catalytic azidation has increased in importance to access enantioenriched nitrogen containing molecules, but methods that employ inexpensive sodium azide remain scarce. This encouraged us to undertake a detailed study on the application of hydrogen bonding phase-transfer catalysis (HB-PTC) to enantioselective azidation with sodium azide. So far, this phase-transfer manifold has been applied exclusively to insoluble metal alkali fluorides for carbon-fluorine bond formation. Herein, we disclose the asymmetric ring opening of meso aziridinium electrophiles derived from ß-chloroamines with sodium azide in the presence of a chiral bisurea catalyst. The structure of novel hydrogen bonded azide complexes was analyzed computationally, in the solid state by X-ray diffraction, and in solution phase by 1H and 14N/15N NMR spectroscopy. With N-isopropylated BINAM-derived bisurea, end-on binding of azide in a tripodal fashion to all three NH bonds is energetically favorable, an arrangement reminiscent of the corresponding dynamically more rigid trifurcated hydrogen-bonded fluoride complex. Computational analysis informs that the most stable transition state leading to the major enantiomer displays attack from the hydrogen-bonded end of the azide anion. All three H-bonds are retained in the transition state; however, as seen in asymmetric HB-PTC fluorination, the H-bond between the nucleophile and the monodentate urea lengthens most noticeably along the reaction coordinate. Kinetic studies corroborate with the turnover rate limiting event resulting in a chiral ion pair containing an aziridinium cation and a catalyst-bound azide anion, along with catalyst inhibition incurred by accumulation of NaCl. This study demonstrates that HB-PTC can serve as an activation mode for inorganic salts other than metal alkali fluorides for applications in asymmetric synthesis.

Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study.

BACKGROUND: There are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab. METHODS: Patients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events. RESULTS: Among 93 patients (0-80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported. CONCLUSIONS: The current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01522170 , January 31, 2012.

Postmenopausal labial agglutination mimics urinary incontinence and hidden vaginal lesion.

Labial agglutination has rarely been reported in postmenopausal women and its treatment has been based on experience with prepubertal girls. We describe an 83-year-old woman who presented with labial agglutination and severe urinary incontinence. She had been treated intermittently with a topical estrogen cream for 3 years, but her symptoms persisted. Surgery was performed and her urinary incontinence was instantly resolved. Incidental vaginal low-grade squamous intraepithelial neoplasia was noted. Later, the lesion progressed and was confirmed to be condyloma acuminata. No recurrence of labial agglutination was noted 3 months after the surgery. We emphasize that surgical intervention should be the first consideration for labial agglutination with urinary symptoms in postmenopausal women. This case also highlights that surgery can not only resolve patients' symptoms early, but can also enable access to the region for essential gynecologic procedures.

Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis.

Atypical haemolytic uraemic syndrome (aHUS) often leads to end-stage renal disease (ESRD) and kidney transplantation; graft loss rates are high due to disease recurrence. A post hoc analysis of four prospective clinical trials in aHUS was performed to evaluate eculizumab, a terminal complement inhibitor, in patients with native or transplanted kidneys. The trials included 26-week treatment and extension periods. Dialysis, transplant and graft loss were evaluated. Study endpoints included complete thrombotic microangiopathy (TMA) response, TMA event-free status, haematologic and renal parameters and adverse events. Of 100 patients, 74 had native kidneys and 26 in the transplant subgroup had a collective history of 38 grafts. No patients lost grafts and only one with pre-existing ESRD received a transplant on treatment. Efficacy endpoints were achieved similarly in both subgroups. After 26 weeks, mean absolute estimated glomerular filtration rate increased from baseline to 61 and 37 ml/min/1.73 m2 in native (n = 71; P < 0.0001) and transplanted kidney (n = 25; P = 0.0092) subgroups. Two patients (one/subgroup) developed meningococcal infections; both recovered, one continued therapy. Eculizumab was well tolerated. Eculizumab improved haematologic and renal outcomes in both subgroups. In patients with histories of multiple graft losses, eculizumab protected kidney function.

Heteroepitaxial Writing of Silicon-on-Sapphire Nanowires.

The heteroepitaxial growth of crystal silicon thin films on sapphire, usually referred to as SoS, has been a key technology for high-speed mixed-signal integrated circuits and processors. Here, we report a novel nanoscale SoS heteroepitaxial growth that resembles the in-plane writing of self-aligned silicon nanowires (SiNWs) on R-plane sapphire. During a low-temperature growth at <350 °C, compared to that required for conventional SoS fabrication at >900 °C, the bottom heterointerface cultivates crystalline Si pyramid seeds within the catalyst droplet, while the vertical SiNW/catalyst interface subsequently threads the seeds into continuous nanowires, producing self-oriented in-plane SiNWs that follow a set of crystallographic directions of the sapphire substrate. Despite the low-temperature fabrication process, the field effect transistors built on the SoS-SiNWs demonstrate a high on/off ratio of >5 × 104 and a peak hole mobility of >50 cm2/V·s. These results indicate the novel potential of deploying in-plane SoS nanowire channels in places that require high-performance nanoelectronics and optoelectronics with a drastically reduced thermal budget and a simplified manufacturing procedure.

Thyroid Nodule Classification in Ultrasound Images by Fine-Tuning Deep Convolutional Neural Network.

With many thyroid nodules being incidentally detected, it is important to identify as many malignant nodules as possible while excluding those that are highly likely to be benign from fine needle aspiration (FNA) biopsies or surgeries. This paper presents a computer-aided diagnosis (CAD) system for classifying thyroid nodules in ultrasound images. We use deep learning approach to extract features from thyroid ultrasound images. Ultrasound images are pre-processed to calibrate their scale and remove the artifacts. A pre-trained GoogLeNet model is then fine-tuned using the pre-processed image samples which leads to superior feature extraction. The extracted features of the thyroid ultrasound images are sent to a Cost-sensitive Random Forest classifier to classify the images into "malignant" and "benign" cases. The experimental results show the proposed fine-tuned GoogLeNet model achieves excellent classification performance, attaining 98.29% classification accuracy, 99.10% sensitivity and 93.90% specificity for the images in an open access database (Pedraza et al. 16), while 96.34% classification accuracy, 86% sensitivity and 99% specificity for the images in our local health region database.

Regulation of drought tolerance by the F-box protein MAX2 in Arabidopsis.

MAX2 (for MORE AXILLARY GROWTH2) has been shown to regulate diverse biological processes, including plant architecture, photomorphogenesis, senescence, and karrikin signaling. Although karrikin is a smoke-derived abiotic signal, a role for MAX2 in abiotic stress response pathways is least investigated. Here, we show that the max2 mutant is strongly hypersensitive to drought stress compared with wild-type Arabidopsis (Arabidopsis thaliana). Stomatal closure of max2 was less sensitive to abscisic acid (ABA) than that of the wild type. Cuticle thickness of max2 was significantly thinner than that of the wild type. Both of these phenotypes of max2 mutant plants correlate with the increased water loss and drought-sensitive phenotype. Quantitative real-time reverse transcription-polymerase chain reaction analyses showed that the expression of stress-responsive genes and ABA biosynthesis, catabolism, transport, and signaling genes was impaired in max2 compared with wild-type seedlings in response to drought stress. Double mutant analysis of max2 with the ABA-insensitive mutants abi3 and abi5 indicated that MAX2 may function upstream of these genes. The expression of ABA-regulated genes was enhanced in imbibed max2 seeds. In addition, max2 mutant seedlings were hypersensitive to ABA and osmotic stress, including NaCl, mannitol, and glucose. Interestingly, ABA, osmotic stress, and drought-sensitive phenotypes were restricted to max2, and the strigolactone biosynthetic pathway mutants max1, max3, and max4 did not display any defects in these responses. Taken together, these results uncover an important role for MAX2 in plant responses to abiotic stress conditions.

Development of a selective and scalable N1-indazole alkylation.

N1-Alkyl indazoles are a ubiquitous and privileged motif within medicinal chemistry, yet methods to selectively furnish N1-alkyl indazoles with simple alkyl side chains remain sparse. Herein, negative data from high-throughput experimentation (HTE) enabled a confident pivot of resource from continued optimisation to the development of an alternative reaction. This workflow culminated in a methodology for the synthesis of N1-alkyl indazoles. The procedure is highly selective for N1-alkylation, practical, and broad in scope, with no N2-alkyl products detected at completion. Mechanistic understandings were consistent with attributing the high selectivity to thermodynamic control. Additional data-driven process development led to this reaction being safely demonstrated on a 100 g scale, with potential for further scale up. This study highlights pragmatic principles followed to develop a necessitated methodology, suitable for large scale manufacture.

Correlation of mucositis during head and neck radiotherapy with computed tomography perfusion imaging of the oropharyngeal mucosa.

OBJECTIVE: The objective of this study was to correlate changes in computed tomography perfusion (CTP) parameters in the oropharyngeal mucosa following start of radiotherapy (RT) with acute mucositis in head and neck cancer patients. METHODS: Fifteen patients were prospectively evaluated with serial CTP imaging. Computed tomography perfusion studies were obtained before RT; at weeks 2, 4, and 6 during RT; and 6 weeks after completion of RT. RESULTS: At week 2 during RT, mean transition time increased to 13.9% and 261.8% in patients with and without mucositis, respectively (P = 0.024). At week 6 of RT, patients with grade 3 mucositis had a 325.4% increase in blood flow compared with a 58.3% increase in patients with grade 0-2 mucositis (P = 0.039). Mean transition time decreased by 29.9% and increased by 187.4% in patients with grade 3 and grade 0-2 mucositis, respectively (P = 0.025). CONCLUSIONS: Mean transition time and blood flow changes in the oropharyngeal mucosa correlated with the incidence and severity of RT-related mucositis.

Lipoprotein phospholipase A2 and cerebral microbleeds in the Framingham Heart Study.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMB) attributable to cerebral amyloid angiopathy generally occur in lobar regions, whereas those attributable to hypertensive vasculopathy are deep. Inflammation may be an underlying mechanism for CMB, with varying associations according to CMB location. Lipoprotein phospholipase-A2 (Lp-PLA2) is a circulating enzyme marker of vascular inflammation associated with risk of ischemic stroke and dementia. We hypothesized that higher Lp-PLA2 levels would be related to higher prevalence of CMB, with possible regional specificity. METHODS: Framingham Offspring participants aged 65 years or older with available Lp-PLA2 measures and brain magnetic resonance imaging were included. Logistic regression models were used to relate Lp-PLA2 activity and mass to presence of CMB, adjusted for age, sex, medication use (aspirin, anticoagulants, and statins), systolic blood pressure, APOE, current smoking, and diabetes. RESULTS: Eight-hundred nineteen participants (mean age, 73 years; 53% women) were included; 106 (13%) had CMB, 82 (10%) were lobar, and 27 (3%) were deep. We did not observe significant associations of CMB and LpPLA2 measures in multivariable adjusted analyses. However, there was a significant interaction between APOE genotype and Lp-PLA2 activity in their relation to presence of deep CMB (P interaction=0.01). Among persons with APOE ε3/ε3, the odds ratio for deep CMB was 0.95 (confidence interval, 0.59-1.53; P=0.83), whereas among those with at least 1 ε2 or ε4 allele, odds ratio was 3.46 (confidence interval, 1.43-8.36; P=0.006). CONCLUSIONS: In our community-based sample of older adults, there was no significant association of Lp-PLA2 with total or lobar CMB. The association of higher levels of Lp-PLA2 activity with deep CMB among those with at least 1 APOE ε2 or ε4 allele merits replication.

Imaging of cervical lymphadenopathy in children and young adults.

OBJECTIVE: This article describes the role of imaging in evaluating cervical lymphadenopathy in patients from birth to their mid-20s, illustrates imaging features of normal and abnormal lymph nodes, and highlights nodal imaging features and head and neck findings that assist in diagnosis. CONCLUSION: Cervical lymph node abnormalities are commonly encountered clinically and on imaging in children and young adults. Although imaging findings can lack specificity, nodal characteristics and associated head and neck imaging findings can assist in determining the underlying cause.

Protective effect of dried safflower petal aqueous extract and its main constituent, carthamus yellow, against lipopolysaccharide-induced inflammation in RAW264.7 macrophages.

BACKGROUND: Safflower, whose botanic name is Carthamus tinctorius L., is a member of the family Compositae or Asteraceae. Carthamus yellow (CY) is the main constituent of safflower and is composed of safflomin A and safflomin B. Dried safflower petals are used in folk medicine and have been shown to invigorate blood circulation, break up blood stasis, and promote menstruation. In addition, dried safflower petals contain yellow dyes that are used to color food and cosmetics. In this study, we investigated the effects of dried safflower petals aqueous extracts (SFA) and CY on lipopolysaccharide (LPS)-induced inflammation using RAW264.7 macrophages. RESULTS: Our data showed that treatment with SFA (1-1000 microg mL(-1)) and CY (1-2000 microg mL(-1)) does not cause cytotoxicity in cells. SFA and CY inhibited LPS-stimulated nitric oxide (NO), prostaglandin E(2) (PGE(2)), and interleukin 1ß (IL-1ß) release, through attenuation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression. Further, SFA and CY suppressed the LPS-induced phosphorylation of nuclear factor-κB, which was associated with the inhibition of IκB-α degradation. CONCLUSION: These results suggest that SFA and CY provide an anti-inflammatory response through inhibiting the production of NO and PGE(2) by the downregulation of iNOS and COX-2 gene expression. Thus safflower petals have the potential to provide a therapeutic approach to inflammation-associated disorders.

Hypocalcemia in a Patient With Metastatic Prostate Cancer From Denosumab Treatment.

Denosumab is a humanized monoclonal antibody that binds RANKL to inhibit osteoclast activity. It is indicated for the prevention of skeletal-related events (SRE) in patients with solid tumors who have bone metastasis and in patients with multiple myeloma. Hypocalcemia is one of the known side effects of denosumab, which can be prevented with calcium supplementation. We present a case of a 72-year-old male with diagnosed metastatic prostate cancer who had received one dose of denosumab 10 days prior to presentation with fatigue, insomnia, and somnolence. His labs showed severe (Grade 4) hypocalcemia, which improved with intravenous calcium supplementation. This case highlights a known but life-threatening side effect of denosumab and the potential need for prolonged calcium monitoring in patients placed on the drug.

Lumbar intrathecal administration of the quaternary lidocaine derivative, QX-314, produces irritation and death in mice.

BACKGROUND: We recently found that peripheral administration of the quaternary lidocaine derivative, QX-314, produces long-lasting sensory and motor blockade in animals. The goal of this study was to test whether intrathecal QX-314 has similar properties. METHODS: We conducted a randomized, double-controlled, blinded study with female CD-1 mice. Animals in the treatment group received lumbar intrathecal QX-314 (0.5-10 mM; volume, 2 microl; each concentration, n = 6). Normal saline and lidocaine (70 mM) served as negative and positive controls (each group, n = 12), respectively. Animals were tested for up to 3 h for lumbosacral neural blockade and observed for adverse effects. RESULTS: No animal injected with saline and 11 of 12 (92%) animals injected with lidocaine displayed reversible lumbosacral motor blockade (P < 0.001). QX-314 (5 mM) produced motor blockade in four of the six (67%) and sensory blockade in five of the six animals (83%; P < 0.05 vs. saline). However, six of the six mice (100%) at 5 mM QX-314 and five of the six (83%) at 10 mM exhibited marked irritation; one of the six animals at 5 mM (17%) and two of the six at 10 mM (33%) died. We observed no neural blockade without adverse effects in any animal injected with QX-314. All animals injected with saline and 11 of the 12 (92%) animals injected with lidocaine demonstrated normal behavior. CONCLUSION: Lumbar intrathecal QX-314 concentration-dependently produced irritation and death in mice, at lower concentrations than those associated with robust motor blockade. Although QX-314 did produce long-lasting neural blockade, these findings indicate that QX-314 is unlikely to be a suitable candidate for spinal anesthesia in humans.

Brachial plexus contouring with CT and MR imaging in radiation therapy planning for head and neck cancer.

With the increasing use of intensity-modulated radiation therapy (IMRT) for the treatment of head and neck cancer, radiation oncologists are expected to have an in-depth knowledge of the computed tomographic (CT) and magnetic resonance (MR) imaging anatomy of this region to be able to accurately characterize tumor extent and define organs at risk for potential radiation injury. The brachial plexus is a complex anatomic structure in the head and neck adjacent to diseased nodes and elective nodal volumes (ie, nodal areas that are prophylactically treated because they are at high risk for micrometastatic disease) and should, therefore, be carefully identified and contoured at CT prior to IMRT planning. A number of multi-institutional protocols mandate contouring the brachial plexus as an "avoidance structure" (ie, a structure or volume that is at risk for complications of radiation therapy) in the planning of head and neck radiation therapy, and, although little information exists on the best method of doing so consistently, contouring may be facilitated with fusion CT-MR imaging software. With three-dimensional conformal radiation therapy, the brachial plexus is not routinely contoured; therefore, its dose limits are not evaluated in treatment planning. In contrast, with IMRT, tolerance doses can be set to limit the maximum dose to the brachial plexus to 60 Gy in most radiation protocols, although the true radiation tolerance dose in patients with head and neck cancer has been mentioned only sporadically in the literature. Additional studies will be required to determine if identification of the brachial plexus as an avoidance structure prior to radiation therapy planning improves treatment outcome in patients with head and neck cancer and reduces long-term toxicity in this structure.

Analgesic properties of the novel amino acid, isovaline.

BACKGROUND: Isovaline, a nonproteinogenic alpha-amino acid rarely found in the biosphere, is structurally similar to the inhibitory neurotransmitters glycine and gamma-aminobutyric acid. Because glycine(A) and gamma-aminobutyric acid receptor agonists are antiallodynic, we hypothesized that isovaline produces antinociception in mice. METHODS: All experiments were performed on female CD-1 mice using a blinded, randomized, and controlled design. The effects of RS-isovaline were studied on nociceptive responses to (1) formalin injection into the hindpaw; (2) glutamate injection into the hindpaw; and (3) strychnine injection either into the lumbar intrathecal space or cisterna magna. We determined the effects of IV RS-isovaline (50, 150, or 500 mg/kg; n = 10/dose) or intrathecal RS-, R-, and S-isovaline, glycine, and beta-alanine into the lumbar intrathecal space (5-microL volumes of 60, 125, 250, and 500 mM; n = 9/dose/group) on the response to formalin in the paw. The response to 20 microL intraplantar glutamate (750 mM) was compared with glutamate (750 mM) coadministered with isovaline. We also determined the response to intraplantar strychnine. Lumbar intrathecal (100 microM) or intracisternal (200 microM) injections of strychnine into the lumbar intrathecal space or the cisterna magna were used to induce allodynia as a measure of glycine inhibitory dysfunction. The effects of intrathecal or intracisternal strychnine were compared with isovaline coapplied with the strychnine (n = 8/group). RESULTS: In the formalin paw test, IV isovaline did not change phase I but decreased phase II responses in a dose-dependent manner (50% effective dose = 66 mg/kg, n = 10, P < 0.01). There was no effect on rotarod performance, appearance, or behavior of the mouse, and no respiratory depression. Intrathecal isovaline, glycine, and beta-alanine attenuated phase I and II responses (P < 0.01 for each drug). In contrast to beta-alanine and glycine, isovaline at maximally effective doses did not produce scratching, biting, or agitation. Intrathecal RS- and S-isovaline attenuated phase I (P < 0.05 for each group) and RS-, R-, and S-isovaline attenuated phase II responses (P < 0.05 for each group), with no significant difference between the efficacies of R- and S-enantiomers. Localized strychnine-induced glycine inhibitory dysfunction was greatly reduced by intracisternal (P < 0.01) and intrathecal (P < 0.01) isovaline. Although intraplantar strychnine did not induce peripheral allodynia, high doses of isovaline did not block the peripheral allodynia induced by glutamate. CONCLUSIONS: Isovaline reduced responses in mouse pain models without producing acute toxicity, possibly by enhancing receptor modulation of nociceptive information.

Effects of local tramadol administration on peripheral glutamate-induced nociceptive behaviour in mice.

PURPOSE: The use of peripheral tramadol to block pain has been advocated. However, since its actions in the periphery have not been elucidated fully, we tested the hypothesis that peripheral tramadol blocks peripheral glutamate-induced nociceptive behaviour in mice. METHODS: First, we compared the duration of paw licking after intraplantar (ipl.) glutamate administration, with and without tramadol, using a randomized blinded controlled design. Next, we established the half maximal effective concentrations (EC(50s)) for local tramadol and reference compound lidocaine in the hot water tail-flick latency test and the glutamate-induced paw allodynia assay. RESULTS: Tramadol reduced glutamate-induced paw licking from 33 +/- 12 sec to 4 +/- 4 sec (mean +/- SD; t test, P < 0.05; n = 6 per group). The tramadol and lidocaine EC(50) nerve conduction blocks in the tail did not differ significantly (84 +/- 24 mM vs 69 +/- 5 mM, respectively). Although tramadol reduced glutamate-induced allodynia (EC(50), 46 +/- 13 mM), lidocaine was more potent (EC(50), 13 +/- 5 mM; Dixon's up-and-down method; P < 0.05). Tramadol was 2.5 times as effective at blocking nerve conduction in the tail compared with allodynia in the paw. CONCLUSIONS: Local tramadol administration blocked nociceptive behaviour in mice induced by peripheral glutamate. Compared with lidocaine, the relative potency of tramadol was lower for blocking glutamate-induced allodynia than for sensory nerve conduction blockade, suggesting the activation of a pronociceptive receptor system in the periphery.

QX-314 produces long-lasting local anesthesia modulated by transient receptor potential vanilloid receptors in mice.

BACKGROUND: The quaternary lidocaine derivative QX-314 is now known to produce long-lasting local anesthesia despite its positive charge. However, recent research suggests that the transient receptor potential vanilloid receptor agonist, capsaicin, should reduce the onset and offset times, whereas the transient receptor potential vanilloid receptor antagonist, capsazepine, should delay the onset time of sensory blockade by QX-314. METHODS: Sensory blockade in the tail of the conscious mouse was investigated using QX-314 2.5% in combination with capsaicin 0.1% and/or capsazepine (50 microg/ml). After tail injection, onset and offset times of local anesthesia were measured using the hot water tail-flick latency test. RESULTS: Capsaicin reduced the onset time of local anesthesia by QX-314 by more than 75% (Mann-Whitney test, P = 0.007; n = 10 per group) with no effect on the offset time of QX-314. For QX-314 without capsaicin, the onset and offset times were 23 min (interquartile range 15-30 min) and 300 min (interquartile range 285-375 min), respectively. For QX-314 with capsaicin, the onset and offset times were 4 min (interquartile range 3-8 min) and 360 min (interquartile range 285-435 min), respectively. In the antagonist study, capsazepine without added capsaicin decreased QX-314's efficacy, as 6 out of 9 mice did not develop sensory blockade after 90 min (Fisher exact test, P = 0.009). CONCLUSION: We have confirmed in a sensory blockade model that QX-314 is a local anesthetic with a slow onset and a long duration of reversible blockade. Capsaicin, a transient receptor potential vanilloid receptor agonist, accelerated QX-314's onset kinetics, whereas capsazepine, a transient receptor potential vanilloid receptor antagonist, decreased QX-314's efficacy. These observations raise the possibility that endovanilloids may modulate cell entry of QX-314.

Labyrinthitis ossificans in a child with sickle cell disease: CT and MRI findings.

The association between sensorineural hearing loss and sickle cell disease has been described, and labyrinthine hemorrhage has been reported with sickle cell disease. We report the CT and MRI findings of labyrinthitis ossificans in a child with sickle cell disease who presented with sensorineural hearing loss. Labyrinthitis ossificans is associated with an infectious, inflammatory, or destructive insult to the membranous labyrinth; however, it has not been specifically described with sickle cell disease. Recognition of this condition is important because it affects both management and prognosis of this disease.

Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study.

BACKGROUND: Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). METHODS: In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated. RESULTS: Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment. CONCLUSIONS: As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.