Promise of Composite Pain Index as a single pain outcome for sickle cell disease across the lifespan.

BACKGROUND: This study aimed to validate a Composite Pain Index (CPI) as a single pain outcome measure for sickle cell disease (SCD) across the lifespan from 8 years of age. PROCEDURE: This prospective, cross-sectional study included 55 participants with SCD who completed the PAINReportIt tool and Adolescent Pediatric Pain Tool (APPT) in random order during outpatient visits to derive respective CPI scores for comparison. RESULTS: Of the 55 participants with SCD, 46 (84%) had HgbSS, eight (15%) HgbSC, and one (2%) HgbSß0+. The mean age of all participants was 17.5 ± 2.6 years, and 28 (51%) were female, 52 (95%) were Black, 42 (98%) were non-Hispanic, and 39 (71%) had a ninth grade or higher education. Correlation analyses between the APPT and PAINReportIt revealed positive associations for the number of pain sites (r = .57, p < .001), pain intensity (r = .46, p < .001), pain quality (r = .74, p < .001), and pain pattern (r = .34, p = .01). Patients' mean CPI scores derived from the PAINReportIt was slightly higher than the APPT; 34.2 (SD = 14.7) and 30.0 (SD = 19.0), respectively. Regression analyses showed that the APPT CPI significantly predicted the PAINReportIt CPI (B = .497, t(53) = 6.051, p < .001). This finding holds true even when accounting for the order of measurement or patient's age. CONCLUSION: The initial validation of CPI as a single pain outcome measure represents a significant advancement in pain assessment for SCD. Further validation is warranted for the CPI as a measure is for both clinicians and researchers to enable longitudinal pain assessment from age 8 years across the lifespan as children age into adult care.

Changes in gut microbial metagenomic pathways associated with clinical outcomes after the elimination of malabsorbed sugars in an IBS cohort.

Specific diets to manage sugar malabsorption are reported to reduce clinical symptoms of irritable bowel syndrome (IBS). However, the effects of diets for malabsorbed sugars on gut microbiota signatures have not been studied, and associations with clinical outcomes in IBS have not been characterized. 22 IBS patients positively tested for either lactose-, fructose-, sorbitol- or combined malabsorptions were subjected to 2-weeks sugar elimination and subsequent 4-weeks re-introduction. 7 IBS patients tested negative for sugar malabsorption were used as controls. Nutrition and clinical symptoms were recorded throughout the study. Fecal samples were serially collected for 16S rRNA amplicon and shotgun-metagenome sequencing. Dietary intervention supervised by nutrition counseling reduced IBS symptoms during the elimination and tolerance phases. Varying clinical response rates were observed between subjects, and used to dichotomize our cohort into visual analogue scale (VAS) responders and non-responders. Alpha -and beta-diversity analyzes revealed only minor differences regarding 16S rRNA-based fecal microbiota compositions between responder and non-responder patients during baseline or tolerance phase. In shotgun-metagenome analyzes, however, we analyzed microbial metabolic pathways and found significant differences in pathways encoding starch degradation and complex amino acid biosynthesis at baseline between IBS controls and malabsorbers, and notably, between diet responder and non-responders. Faecalibacterium prausnitzii, Ruminococcus spp. and Bifidobacterium longum largely informed these metabolic pathways. Our study demonstrates that diet interventions for specific, malabsorbed carbohydrates reshaped the metagenomic composition of the gut microbiota, with a small community of bacterial taxa contributing to these changes rather than a single species.

Primary and Secondary Stroke Prevention in Children With Sickle Cell Disease.

Children with sickle cell disease (SCD) have numerous acute and chronic complications, including central nervous system (CNS) disease, which can be debilitating over their life span. Recognition of risk factors for CNS disease and overt CNS disease should be properly identified by primary care providers, including physicians, physician assistants, and nurse practitioners. Here, we discuss an emerging and important early indicator of CNS disease in the form of silent cerebral infarcts and review overt stroke in patients with SCD. We also discuss transcranial Doppler ultrasonography, when and how often transcranial Doppler ultrasounds should be performed, and management of abnormal results. Lastly, we review the clinical data for the management and prevention of silent cerebral infarcts and overt stroke in children with SCD.

Structural, electronic and vibrational properties of few-layer 2H- and 1T-TaSe2.

Two-dimensional metallic transition metal dichalcogenides (TMDs) are of interest for studying phenomena such as charge-density wave (CDW) and superconductivity. Few-layer tantalum diselenides (TaSe2) are typical metallic TMDs exhibiting rich CDW phase transitions. However, a description of the structural, electronic and vibrational properties for different crystal phases and stacking configurations, essential for interpretation of experiments, is lacking. We present first- principles calculations of structural phase energetics, band dispersion near the Fermi level, phonon properties and vibrational modes at the Brillouin zone center for different layer numbers, crystal phases and stacking geometries. Evolution of the Fermi surfaces as well as the phonon dispersions as a function of layer number reveals dramatic dimensionality effects in this CDW material. Our results indicate strong electronic interlayer coupling, detail energetically possible stacking geometries, and provide a basis for interpretation of Raman spectra.

Prevalence of pain-related single nucleotide polymorphisms in patients of African origin with sickle cell disease.

BACKGROUND: Prospective pain genetics research is hindered by a lack of data on the prevalence of polymorphisms in pain-relevant genes for patients with sickle cell disease (SCD). For African-Americans in general, limited information is available in public databases. METHODS: We prioritized and examined the genotype and allele frequencies of 115 SNPs from 49 candidate pain genes in 199 adult African-Americans and pediatric patients of African origin with SCD. Analyses were performed and compared with available data from public databases. RESULTS: Genotype and allele frequencies of a number of SNPs were found to be different between our cohort and those from the databases and between adult and pediatric subjects. CONCLUSION: As pain therapy is inadequate in a significant percentage of patients with SCD, candidate pain genetic studies may aid in designing precision pain medicine. We provide prevalence data as a reference for prospective genetic studies in this population.

Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7.

Platelets store and release CXCL12 (SDF-1), which governs differentiation of hematopoietic progenitors into either endothelial or macrophage-foam cells. CXCL12 ligates CXCR4 and CXCR7 and regulates monocyte/macrophage functions. This study deciphers the relative contribution of CXCR4-CXCR7 in mediating the effects of platelet-derived CXCL12 on monocyte function, survival, and differentiation. CXCL12 and macrophage migration inhibitory factor (MIF) that ligate CXCR4-CXCR7 induced a dynamic bidirectional trafficking of the receptors, causing CXCR4 internalization and CXCR7 externalization during chemotaxis, thereby influencing relative receptor availability, unlike MCP-1. In vivo we found enhanced accumulation of platelets and platelet-macrophage co-aggregates in peritoneal fluid following induction of peritonitis in mice. The relative surface expression of CXCL12, CXCR4, and CXCR7 among infiltrated monocytes was also enhanced as compared with peripheral blood. Platelet-derived CXCL12 from collagen-adherent platelets and recombinant CXCL12 induced monocyte chemotaxis specifically through CXCR4 engagement. Adhesion of monocytes to immobilized CXCL12 and CXCL12-enriched activated platelet surface under static and dynamic arterial flow conditions were mediated primarily through CXCR7 and were counter-regulated by neutralizing platelet-derived CXCL12. Monocytes and culture-derived-M1-M2 macrophages phagocytosed platelets, with the phagocytic potential of culture-derived-M1 macrophages higher than M2 involving CXCR4-CXCR7 participation. CXCR7 was the primary receptor in promoting monocyte survival as exerted by platelet-derived CXCL12 against BH3-mimetic induced apoptosis (phosphatidylserine exposure, caspase-3 activation, loss of mitochondrial transmembrane potential). In co-culture experiments with platelets, monocytes predominantly differentiated into CD163(+) macrophages, which was attenuated upon CXCL12 neutralization and CXCR4/CXCR7 blocking antibodies. Moreover, OxLDL uptake by platelets induced platelet apoptosis, like other platelet agonists TRAP and collagen-related peptide (CRP). CXCL12 facilitated phagocytosis of apoptotic platelets by monocytes and M1-M2 macrophages, also promoted their differentiation into foam cells via CXCR4 and CXCR7. Thus, platelet-derived CXCL12 could regulate monocyte-macrophage functions through differential engagement of CXCR4 and CXCR7, indicating an important role in inflammation at site of platelet accumulation.

Platelet surface expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 is associated with clinical outcomes in patients with coronary artery disease.

BACKGROUND: Surface expression of stromal cell-derived factor-1 (SDF-1, CXCL12) on platelets is enhanced during ischemic events and plays an important role in peripheral homing of stem cells and myocardial repair mechanisms. SDF-1 effects are mediated through CXCR4 and CXCR7. Both CXCR4 and CXCR7 are surface expressed on human platelets and to a higher degree in patients with coronary artery disease (CAD) compared with healthy controls. In this study, we investigated the prognostic role of platelet CXCR4- and CXCR7 surface expression in patients with symptomatic CAD. METHODS AND RESULTS: In a cohort study, platelet surface expression of CXCR4 and CXCR7 was measured by using flow cytometry in 284 patients with symptomatic CAD at the time of percutaneous coronary intervention (PCI). The primary combined end point was defined as all-cause death and/or myocardial infarction (MI) during 12-month follow-up. Secondary end points were defined as the single events of all-cause death and MI. We found significant differences of CXCR4 values in patients who developed a combined end point compared with event-free patients (mean MFIAUTHOR: Please define MFI at first use. 3.17 vs. 3.44, 95% confidence interval [CI] 0.09-0.45) and in patients who subsequently died (mean MFI 3.10 vs. 3.42, 95% CI 0.09-0.56). In multivariate Cox regression analysis, lower platelet CXCR4 levels were independently and significantly associated with all-cause mortality (hazard ratio 0.24, 95% CI 0.07-0.87) and the primary combined end point of all-cause death and/or MI (hazard ratio 0.30, 95% CI 0.13-0.72). CONCLUSION: These findings highlight a potential prognostic value of platelet expression CXCR4 on clinical outcomes in patients with CAD.

Condensation transition and forced unravelling of DNA-histone H1 toroids: a multi-state free energy landscape.

DNA is known to condense with multivalent cations and positively charged proteins. However, the properties and energetics of DNA superstructures, such as chromatin, are poorly understood. As a model system, we investigate histone H1 condensation of DNA with tethered particle motion and force-extension measurements. We show that after the addition of H1 to DNA, a concentration dependent lag time is followed by the DNA spontaneously condensing. The trigger for this condensation phase transition can be modeled as sufficient H1s having bound to the DNA, providing insight into the 30 nm fiber condensation upon H1 binding. Furthermore, optical tweezers force-extension measurements of histone H1 condensed DNA reveals a sequence of state transitions corresponding to the unwinding of superhelical turns. We determine the complete, experimental, multi-state free energy landscape for the complex using Crooks fluctuation theorem. The measured force-versus-extension and free energy landscape are compared to predictions from a simple, theoretical model. This work encourages the theoretical description of DNA/protein structure and energetics and their role in chromatin and other, more complex, systems.

Hydroxyurea therapy for priapism prevention and erectile function recovery in sickle cell disease: a case report and review of the literature.

Prolonged ischemic priapism in patients with sickling hemoglobinopathies is a urologic emergency requiring immediate intervention to avoid irreversible anoxic penile injury, corporal fibrosis, and erectile dysfunction. Therapeutic options, however, are limited and often ineffective. Here, we report recovery of erectile function with hydroxyurea therapy in an adolescent with hemoglobin SS following a prolonged episode of priapism and subsequent severe erectile dysfunction. This case suggests a potential role of hydroxyurea in reversing end organ damage in patients with hemoglobin SS and also supports basic science work indicating involvement of the NO-dependent pathway in the pathogenesis of sickle cell disease-associated priapism.

Adolescent pediatric pain tool for multidimensional measurement of pain in children and adolescents.

Very few multidimensional tools are available for measurement of pain in children and adolescents. We critically reviewed the scientific literature to examine the psychometrics and utility of the Adolescent Pediatric Pain Tool (APPT), a multidimensional self-report tool that evaluates the intensity, location, and quality (including affective, evaluative, sensory, and temporal) dimensions of pain. The APPT is available in English and Spanish for children and adolescents, and was modeled after the McGill Pain Questionnaire in adults. We found good evidence for construct validity, reliability, and sensitivity of the APPT for the measurement of pediatric pain. The APPT was used to measure pain in children with different conditions, such as cancer, sickle cell disease, orthopedic, traumatic injuries, and allergy testing. Although the APPT was designed to assess the multiple dimensions of pain, the majority of the reports included results only for the intensity ratings. Unlike the numerical and pediatric faces rating scales, which are widely used in clinical practice and research, the APPT is not limited to the single dimension of pain intensity. It measures multiple dimensions, and may be able to discriminate between nociceptive and neuropathic pain. The APPT is one of a few multidimensional pain measures that can help to advance the science of pediatric pain and its management. When the APPT is used in practice or research, the multiple dimensions of pain may be characterized and compared in different painful conditions. It may guide the use of multimodal interventions in children and adolescents with a variety of pain conditions.

Validation of OpenFoam for heavy gas dispersion applications.

In the present paper heavy gas dispersion calculations were performed with OpenFoam. For a wind tunnel test case, numerical data was validated with experiments. For a full scale numerical experiment, a code to code comparison was performed with numerical results obtained from Fluent. The validation was performed in a gravity driven environment (slope), where the heavy gas induced the turbulence. For the code to code comparison, a hypothetical heavy gas release into a strongly turbulent atmospheric boundary layer including terrain effects was selected. The investigations were performed for SF6 and CO2 as heavy gases applying the standard k-ɛ turbulence model. A strong interaction of the heavy gas with the turbulence is present which results in a strong damping of the turbulence and therefore reduced heavy gas mixing. Especially this interaction, based on the buoyancy effects, was studied in order to ensure that the turbulence-buoyancy coupling is the main driver for the reduced mixing and not the global behaviour of the turbulence modelling. For both test cases, comparisons were performed between OpenFoam and Fluent solutions which were mainly in good agreement with each other. Beside steady state solutions, the time accuracy was investigated. In the low turbulence environment (wind tunnel test) which for both codes (laminar solutions) was in good agreement, also with the experimental data. The turbulent solutions of OpenFoam were in much better agreement with the experimental results than the Fluent solutions. Within the strong turbulence environment, both codes showed an excellent comparability.

The molecular yo-yo method: live jump detection improves throughput of single-molecule force spectroscopy for out-of-equilibrium transitions.

By monitoring multiple molecular transitions, force-clamp, and trap-position-clamp methods have led to precise determinations of the free energies and free energy landscapes for molecular states populated in equilibrium at the same or similar forces. Here, we present a powerful new elaboration of the force-clamp and force-jump methods, applicable to transitions far from equilibrium. Specifically, we have implemented a live jump detection and force-clamp algorithm that intelligently adjusts and maintains the force on a single molecule in response to the measured state of that molecule. We are able to collect hundreds of individual molecular transitions at different forces, many times faster than previously, permitting us to accurately determine force-dependent lifetime distributions and reaction rates. Application of our method to unwinding and rewinding the nucleosome inner turn, using optical tweezers reveals experimental lifetime distributions that comprise a statistically meaningful number of transitions, and that are accurately single exponential. These measurements significantly reduce the error in the previously measured rates, and demonstrate the existence of a single, dominant free energy barrier at each force studied. A key benefit of the molecular yo-yo method for nucleosomes is that it reduces as far as possible the time spent in the tangentially bound state, which minimizes the loss of nucleosomes by dissociation.

Clinical practice guideline: improving voice outcomes after thyroid surgery.

OBJECTIVE: Thyroidectomy may be performed for clinical indications that include malignancy, benign nodules or cysts, suspicious findings on fine needle aspiration biopsy, dysphagia from cervical esophageal compression, or dyspnea from airway compression. About 1 in 10 patients experience temporary laryngeal nerve injury after surgery, with longer lasting voice problems in up to 1 in 25. Reduced quality of life after thyroid surgery is multifactorial and may include the need for lifelong medication, thyroid suppression, radioactive scanning/treatment, temporary and permanent hypoparathyroidism, temporary or permanent dysphonia postoperatively, and dysphagia. This clinical practice guideline provides evidence-based recommendations for management of the patient's voice when undergoing thyroid surgery during the preoperative, intraoperative, and postoperative period. PURPOSE: The purpose of this guideline is to optimize voice outcomes for adult patients aged 18 years or older after thyroid surgery. The target audience is any clinician involved in managing such patients, which includes but may not be limited to otolaryngologists, general surgeons, endocrinologists, internists, speech-language pathologists, family physicians and other primary care providers, anesthesiologists, nurses, and others who manage patients with thyroid/voice issues. The guideline applies to any setting in which clinicians may interact with patients before, during, or after thyroid surgery. Children under age 18 years are specifically excluded from the target population; however, the panel understands that many of the findings may be applicable to this population. Also excluded are patients undergoing concurrent laryngectomy. Although this guideline is limited to thyroidectomy, some of the recommendations may extrapolate to parathyroidectomy as well. RESULTS: The guideline development group made a strong recommendation that the surgeon should identify the recurrent laryngeal nerve(s) during thyroid surgery. The group made recommendations that the clinician or surgeon should (1) document assessment of the patient's voice once a decision has been made to proceed with thyroid surgery; (2) examine vocal fold mobility, or refer the patient to a clinician who can examine vocal fold mobility, if the patient's voice is impaired and a decision has been made to proceed with thyroid surgery; (3) examine vocal fold mobility, or refer the patient to a clinician who can examine vocal fold mobility, once a decision has been made to proceed with thyroid surgery if the patient's voice is normal and the patient has (a) thyroid cancer with suspected extrathyroidal extension, or (b) prior neck surgery that increases the risk of laryngeal nerve injury (carotid endarterectomy, anterior approach to the cervical spine, cervical esophagectomy, and prior thyroid or parathyroid surgery), or (c) both; (4) educate the patient about the potential impact of thyroid surgery on voice once a decision has been made to proceed with thyroid surgery; (5) inform the anesthesiologist of the results of abnormal preoperative laryngeal assessment in patients who have had laryngoscopy prior to thyroid surgery; (6) take steps to preserve the external branch of the surperior laryngeal nerve(s) when performing thyroid surgery; (7) document whether there has been a change in voice between 2 weeks and 2 months following thyroid surgery; (8) examine vocal fold mobility or refer the patient for examination of vocal fold mobility in patients with a change in voice following thyroid surgery; (9) refer a patient to an otolaryngologist when abnormal vocal fold mobility is identified after thyroid surgery; (10) counsel patients with voice change or abnormal vocal fold mobility after thyroid surgery on options for voice rehabilitation. The group made an option that the surgeon or his or her designee may monitor laryngeal electromyography during thyroid surgery. The group made no recommendation regarding the impact of a single intraoperative dose of intravenous corticosteroid on voice outcomes in patients undergoing thyroid surgery.

Alloimmunization in sickle cell anemia in the era of extended red cell typing.

BACKGROUND: Red blood cell (RBC) transfusion remains an essential part of the management of patients with sickle cell disease (SCD). Alloimmunization is a major complication of transfusions. Extended RBC typing is advocated as a means to reduce alloimmunization in SCD. Our goal was to assess alloimmunization among individuals with SCD at our center since implementing extended RBC typing. MATERIALS AND METHODS: We reviewed electronic medical records of all patients with SCD (N = 641) in our comprehensive SCD Program to determine transfusion histories. Cross-referencing with our blood bank database, we extracted data such as antibodies identified, detection date and genotyping in specific cases. Transfusion sources were determined for those with C, E, and Kell antibodies. RESULTS: Of 180 patients transfused from 2002 to 2011, 26 developed at least one new antibody. The majority of alloimmunized patients (14/26) received episodic transfusions only. The most common antibodies formed were against C and E antigens. Of the 16 patients who developed C, E, Kell antibodies, nine had one or more documented transfusions at an outside hospital. Five patients had Rh variants undetectable on routine phenotyping including two novel e alleles related to ceAR and ce(S)(733G). CONCLUSION: Despite extended RBC typing, alloimmunization may still occur due to RBC variants that are not detected on routine screening and transfusions at institutions where extended RBC typing is not done. Extended RBC typing should be the standard of care for patients with SCD. Prospective genotyping may reduce allosensitization to rare variants not detected on routine screening.

Unwinding and rewinding the nucleosome inner turn: force dependence of the kinetic rate constants.

A simple model for the force-dependent unwinding and rewinding rates of the nucleosome inner turn is constructed and quantitatively compared to the results of recent measurements [A. H. Mack et al., J. Mol. Biol. 423, 687 (2012)]. First, a coarse-grained model for the histone-DNA free-energy landscape that incorporates both an elastic free-energy barrier and specific histone-DNA bonds is developed. Next, a theoretical expression for the rate of transitions across a piecewise linear free-energy landscape with multiple minima and maxima is presented. Then, the model free-energy landscape, approximated as a piecewise linear function, and the theoretical expression for the transition rates are combined to construct a model for the force-dependent unwinding and rewinding rates of the nucleosome inner turn. Least-mean-squares fitting of the model rates to the rates observed in recent experiments rates demonstrates that this model is able to well describe the force-dependent unwinding and rewinding rates of the nucleosome inner turn, observed in the recent experiments, except at the highest forces studied, where an additional ad hoc term is required to describe the data, which may be interpreted as an indication of an alternate high-force nucleosome disassembly pathway, that bypasses simple unwinding. The good agreement between the measurements and the model at lower forces demonstrates that both specific histone-DNA contacts and an elastic free-energy barrier play essential roles for nucleosome winding and unwinding, and quantifies their relative contributions.

Shwachman-Diamond syndrome: diarrhea, no longer required?

Exocrine pancreatic insufficiency and diarrhea have been hallmarks in the diagnosis of Shwachman-Diamond syndrome (SDS). We report 2 cases of genetically confirmed SDS in patients who presented with an unusual phenotype. Patient #1 presented with pancytopenia without other system involvement, while patient #2 presented with severe neutropenia, anemia, and a bifid thumb. Neither patient had diarrhea or malabsorption. Both patients had the classic heterozygous mutations c183_184 TA>CT and c.258+2 T>C in the Shwachman-Bodian-Diamond syndrome gene. Incomplete phenotypes may be more common than previously recognized in bone marrow failure syndromes; gastrointestinal symptoms should not be considered a prerequisite for SDS.

Practical axial optical trapping.

We describe a new method for calibrating optical trapping measurements in which tension is applied in the direction of the laser beam to a molecule tethered between a surface and an optically trapped bead. Specifically, we present a generally-applicable procedure for converting from the measured scattering intensity and the measured stage displacement to applied tension and bead-coverslip separation, using measurements of the light intensity scattered from an untethered, trapped bead. Our calibration accounts for a number of effects, including aberrations and the interference of forward-reflected bead-scattered light with the trapping beam. To demonstrate the accuracy of our method, we show measurements of the DNA force-versus-extension relation using a range of laser intensities, and show that these measurements match the expected extensible wormlike-chain (WLC) behavior. Finally, we also demonstrate a force-clamp, in which the tension in a tether is held fixed while the extension varies as a result of molecular events.

Gamma knife radiosurgery of recurrent atypical neurocytoma. Case report and review of the literature.

BACKGROUND AND PURPOSE: The goal of this work was to demonstrate the efficacy of stereotactic gamma knife radiosurgery (GKRS) for the treatment of neurocytoma by means of a case report and a comprehensive literature review. CASE REPORT: A locally recurrent atypical neurocytoma in the area of the left third ventricle thalamic wall occurring 7 years after primary microsurgical resection in a 59-year old woman was treated by GKRS. A marginal dose of 17 Gy was delivered to the surrounding 50% isodose. At the last follow-up, 82 months after radiosurgery, the tumor was locally controlled. For the literature review, computerized bibliographic searches of Pubmed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings. DISCUSSION: The present case confirms the results of the literature analysis. From 1997-2011, a total of 14 series were published providing results of GKRS in 86 patients (89 lesions). The marginal doses, which have been applied, ranged from 9.6-20.0 Gy. With median follow-up intervals between 6 and 185 months, local control was 97.2% and local tumor progression of neurocytoma after GKRS was restricted to only 4 cases. In accordance with our own experience, GKRS was not associated with a relevant early or late toxicity. CONCLUSION: GKRS can be assumed to be a safe and effective treatment modality of recurrent or residual neurocytoma.

Opioid patient controlled analgesia use during the initial experience with the IMPROVE PCA trial: a phase III analgesic trial for hospitalized sickle cell patients with painful episodes.

Opioid analgesics administered by patient-controlled analgesia (PCA)are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations,a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI­higher demand dose with low constant infusion or LDHI­lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents,mg/kg) in 22 adults was 11.6 ± 2.6 and 4.7 ± 0.9 in the HDLI andin the LDHI arms, respectively, and in 12 children it was 3.7 ± 1.0 and 5.8 ± 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI0.9 ± 0.1, LDHI 0.9 ± 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage.

All functional aquaporin-4 isoforms are expressed in the rat cochlea and contribute to the formation of orthogonal arrays of particles.

The water channel aquaporin-4 (AQP4) is expressed in the cochlea and is essential for normal hearing. Unlike other AQPs, multiple isoforms of AQP4 have been reported in diverse tissues, three of which, M1, M23, and Mz, function as water channels. In addition, these protein isoforms are found in higher order complexes. Morphologically these higher order complexes correspond to orthogonal arrays of particles (OAPs) that are found in cell membranes by freeze fracture analysis. Using RT-PCR, quantitative PCR and blue-native PAGE immunoblots we identified all functional AQP4 isoforms -M1, M23, and Mz- and the formation of higher-order complexes in the organ of Corti of the rat. Complementary freeze-fracture studies revealed OAPs distributed in the lateral and basal membrane domains of the cochlear duct supporting cells, specifically Hensen's cells and outer sulcus cells. The unique inter- and intracellular heterogeneity in size, density and shape of OAPs suggests exceptional physiological requirements for the maintenance of water homeostasis during auditory sensory transduction in the cochlea.