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.

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.

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.

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.

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.

Asymptomatic colonic histoplasmosis in a patient receiving methotrexate.

Disease due to infection with Histoplasma capsulatum usually manifests as a disseminated infection in patients with the Acquired Immunodeficiency Syndrome (AIDS). However, it may also present with focal disease in patients with or without AIDS. Unusual presentations or less well-recognized risk factors may make diagnosis of histoplasmosis more difficult. We describe the case of a patient who presented for screening colonoscopy and was found to have isolated asymptomatic colonic histoplasmosis.

Apolipoprotein A-I and serum amyloid A plasma levels are biomarkers of acute painful episodes in patients with sickle cell disease.

BACKGROUND: Acute painful episodes are the clinical hallmark of sickle cell disease and have been linked to morbidity and mortality in the sickle cell population. DESIGN AND METHODS: We undertook exploratory proteomic studies on paired plasma samples collected from a cohort of 26 adult sickle cell patients during steady state and on the first day of an acute painful episode. We screened for changes in abundance of specific protein peaks via surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS), and confirmed the identify of candidate protein peaks by specific immunoassays. RESULTS: The levels of hemoglobin, hematocrit, total protein, and albumin were lower and the levels of lactate dehydrogenase and absolute reticulocytes higher during acute painful episodes than during the steady state. Surface-enhanced laser desorption/ionization time of flight mass spectrometry spectral analysis consistently showed a mass-to-charge peak at 11.7 kDa with elevated intensities during acute painful episodes, which correlated significantly with the serum amyloid A immunoassay. Serum amyloid A levels were significantly elevated during acute painful episodes, especially in four patients with marked end-organ complications of such episodes. A second, recurring peak, less abundant during acute painful episodes, was present at 28.1 kDa; this peak was correlated significantly with immunoassay measurements of apolipoprotein A1. CONCLUSIONS: On the average, plasma serum amyloid A rises and apolipoprotein AI falls during acute painful episodes. The serum amyloid A/apolipoprotein AI ratio increased in 81% of the patients during acute painful episodes, potentially making it a useful objective marker of such episodes. We propose that these protein alterations, known to contribute to endothelial dysfunction in other settings, might do likewise acutely in acute painful episodes and present a new target for therapeutic intervention in sickle cell disease. (ClincalTrials.gov Identifier: NCT00081523).

Optical Bragg imaging of acoustic fields after reflection.

Bragg diffraction of x-rays occurs when the rays interact with a crystalline lattice at the appropriate angle. Bragg diffraction of visible light occurs when the light interacts at the Bragg angle with an ultrasonic field of the appropriate frequency. (The spacing between acoustic condensations and rarefactions acts like the planes in an atomic lattice.) If a beam of light is Bragg diffracted by an ultrasonic beam that previously has passed through an object, an image of the structure of the object is made visible in the diffraction field of the optical beam since there is a one-to-one mapping of the ultrasonic field onto the diffraction order. In many acoustic Bragg imaging applications, the sound field must pass through the object which is to be imaged. Ultrasonic attenuation at the very high acoustic frequencies needed for Bragg imaging (typically approximately 25-30 MHz) severely limits the nondestructive testing (NDT) applications of traditional acoustic Bragg imaging. In this paper, a reflection-based application of acoustic Bragg imaging is discussed which may have useful industrial and biomedical NDT applications.

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.

Smooth pursuit eye movements: is perceived motion necessary?

It has recently been shown that perceived motion, in the absence of any appropriate retinal motion, is a sufficient stimulus to generate smooth pursuit eye motions. This raises the question of whether perceived motion is necessary for pursuit. In three experiments we obtained a negative answer to this question: retinal motion always governed pursuit.

Angular and frequency spectral analysis of the ultrasonic backward beam displacement on a periodically grooved solid.

The ultrasonic backward beam displacement, which has been shown to occur when a bounded beam is incident upon a periodically corrugated liquid-solid interface, is studied experimentally. This effect has been previously studied on a periodic water-brass interface at one particular frequency (6 MHz) and one corresponding angle of incidence (22.5 degrees), but the question has remained whether it would also exist at other frequency and angle combinations. The knowledge of whether this phenomenon is a coincidence or whether it will occur for other frequency and angle combinations contributes to a better understanding of the interaction of ultrasound with periodic structures and diffraction effects, in particular. Potential applications exist in the study of phononic crystals and in the non-destructive evaluation of materials. The present work reports results from recent experiments on the same periodically grooved brass sample that was employed in the first investigations of this phenomenon. Through the examination of frequency spectra in the form of angular and classical spectrograms, the experiments reported here show the backward beam displacement to occur for multiple angles of incidence and frequencies. Furthermore, evidence is shown as to the exact cause of the backward beam displacement, namely, a backward propagating Scholte-Stoneley wave.

Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study.

In addition to vaso-occlusion by sickled erythrocytes, the pathophysiology of sickle cell disease (SCD) is compounded by the diminished bioavailability of nitric oxide (NO), associated with vasoconstriction, endothelial activation and cell adhesion. We tested the ability of sodium nitrite, which can be converted to NO by deoxyhaemoglobin at acid pH and low oxygen tension, to improve blood flow in patients with SCD. In a phase I/II clinical trial, sodium nitroprusside, NG-monomethyl-L-arginine, and sodium nitrite were infused sequentially into the brachial artery in 14 patients at steady state. In a dose-dependent manner, sodium nitrite infusion rates of 0.4, 4 and 40 micromol/min into the brachial artery augmented mean venous plasma nitrite concentrations (P < 0.0001) and stimulated forearm blood flow up to 77 +/- 11% above baseline (P < 0.0001), measured by venous occlusion strain gauge plethysmography. This nitrite response was blunted significantly compared to controls without SCD, as previously seen with other NO donors. Sodium nitrite infusions were well tolerated without hypotension, clinically significant methaemoglobinaemia or other untoward events. The unique pharmacological properties of nitrite as a hypoxia-potentiated vasodilator and cytoprotective agent in the setting of ischaemia-reperfusion injury make this anion a plausible NO donor for future clinical trials in SCD.

Evidence for a columnar organization of cones, Müller cells, and neurons in the retina of a cichlid fish.

In the retina of many lower vertebrates, the arrangement of cells, in particular of cone photoreceptors, is highly regular. The data presented in this report show that in the retina of a cichlid fish (Astatotilapia burtoni) the regular arrangement is not restricted to cone photoreceptors and their synaptic terminals but can be found in elements of the inner retina as well. A variety of immunocytochemical and other markers was used in combination with confocal microscopy on whole-mount preparations and tangential sections. Nearest neighbor analysis was performed and density recovery profiles as auto- and cross-correlograms were generated. Cells displaying a regular arrangement of their synaptic processes in matching radial register to each other were identified for each major retinal neuronal cell type except ganglion cells (i.e. photoreceptors, horizontal cells, bipolar cells, and amacrine cells). The precise location of some of the corresponding cell bodies was not as regular but still non-random, however there was no spatial cross-correlation between cell bodies of different types. The radial processes of Müller glial cells displayed a distribution correlating to the arrangement of photoreceptors and neurons. Thus, for one Müller glial cell I found two PKC-positive cone bipolar cells, a spatially corresponding grid of parvalbumin-positive amacrine cell processes, one H1 horizontal cell, and two pairs of double cones. There was no evidence among ganglion cells matching this pattern, possibly due to the lack of suitable markers. Although many other cell types do not follow this matching regular mosaic arrangement, a basic columnar building block can be postulated for the retina at least in cichlid fish. This suggests a functional radial unit from photoreceptors to the inner plexiform layer.

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.

Sickle cell disease and nitric oxide: a paradigm shift?

Traditionally the pathophysiology of sickle cell disease is thought to result from the polymerization of hemoglobin S in red cells, under hypoxic conditions, resulting in the occlusion of blood vessels. Adhesion of cells to the venular endothelium also appears to play a role. Recent studies have also suggested that in addition to the polymerization of hemoglobin S in the red blood cell, a deficiency of the endogenous vasodilator, nitric oxide may be involved. Hemoglobin released as a result of hemolysis rapidly consumes nitric oxide resulting in a whole program of events that inhibit blood flow. Therapies directed at decreasing the destruction of nitric oxide, increasing the production of nitric oxide, or amplifying the nitric oxide response may prove beneficial.

The key role of butyrylcholinesterase during neurogenesis and neural disorders: an antisense-5'butyrylcholinesterase-DNA study.

The wide tissue distribution of butyrylcholinesterase (BChE) in organisms makes specific roles possible, although no clear physiologic function has yet been assigned to this enzyme. In vertebrates, it appears e.g. in serum, hemopoietic cells, liver, lung, heart, at cholinergic synapses, in the central nervous system. in tumors and not at least (besides acetylcholinesterase, AChE) in developing embryonic tissues. Here, a functional role of BChE can be found in regulation of cell proliferation and the onset of differentiation during early neuronal development--independent of its enzymatic activity. For studies concerning this point, we have established a strategy for a specific and efficient inhibition of BChE to investigate how the expected decrease of enzyme and, therefore, the manipulation of cellular cholinesterase-equilibrium influences embryonic neurogenesis--among others to gain information about the significance of noncholinergic, activity-independent and cell growth functions of BChE. The antisense-5'BChE-DNA strategy is based on inhibition of BChE mRNA transcription and protein synthesis. For this, the BChE gene is cloned into a suitable vector system; this is done in antisense-orientation, so that a transfected cell will produce their own antisense mRNA to inhibit gene expression. For such investigations in neurogenesis, the developing retina is a good model and we are able to create organotypic, three-dimensional retinal aggregates in vitro (retinospheroids) using isolated retinal cells of 6-day-old chicken embryos. Using this in vitro retina and "knock out" of BChE gene expression, we could show a key role of BChE during neurogenesis. The results are of great interest because in tumorigenesis and some neuronal disorders, the BChE gene is amplified or abnormally expressed. It has to be discussed how the antisense-5'BChE strategy can play a role in the development of new and efficient therapy forms.

An ultrasonic Gaussian transducer and its diffraction field: theory and practice.

In this paper, the authors present a novel way to describe the diffraction field for a Gaussian source, which becomes a Gaussian itself. It is described by the Rayleigh surface integral based on the Huygens' theorem. The derivation does not require the parabolic approximation used by previous authors. An improved spherical button Gaussian transducer design also is presented to verify the theory. A theoretical principle of this design based on electromagnetic theory is developed. Both megahertz and kilohertz experimental results show that the sound fields generated by Gaussian transducers of this design agree very well with the theoretical predictions.

Development of a 3-D convolution/superposition algorithm for precise dose calculation in the skull.

In this paper an algorithm for calculating 3-D dose distributions within the brain is introduced and adapted to the demands of modem radiosurgery. The dose calculation with this model is based on a 3-D distribution of the primary photon intensity which is calculated with a ray casting algorithm. A prelocated matrix takes into account field sizes as well as modifying elements as collimator positions (MLC), blocks, wedges and compensators. Monte Carlo precalculated monoenergetic kernels from 0.1 MeV to 50 MeV were at our disposal. The components of the spectrum were either determined by deconvoluting depth dose curves measured in water or analyzed with a Ge-Li detector system in the case of 60Co. The calculated fluence distribution has to be superposed to the complete kernel containing the spatial energy deposition. Inhomogeneities and tissue interface phenomena (rhoe, Z) have been investigated. The divergence of the rays and the curved surface of the patient are taken into account. Assuming homogenous media, it is possible to shorten the computation time by using the Fast Fourier Transformation (FFT) delivering a first overview within seconds. The algorithm was evaluated and verified under specific conditions of small fields as used in radiosurgery and compared to dose measurements and Monte Carlo calculations. In using both the fast algorithm (FFT) for mainly homogenous conditions on one hand and the very precise superposition for inhomogeneous cases on the other, this algorithm can be a very helpful instrument especially for critical locations in the skull.