Literacy-Adapted Cognitive Behavioral Therapy Versus Education for Chronic Pain at Low-Income Clinics: A Randomized Controlled Trial.

Background: Chronic pain is common and challenging to treat. Although cognitive behavioral therapy (CBT) is efficacious, its benefit in disadvantaged populations is largely unknown. Objective: To evaluate the efficacy of literacy-adapted and simplified group CBT versus group pain education (EDU) versus usual care. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT01967342). Setting: Community health centers serving low-income patients in Alabama. Patients: Adults (aged 19 to 71 years) with mixed chronic pain. Interventions: CBT and EDU delivered in 10 weekly 90-minute group sessions. Measurements: Self-reported, postintervention pain intensity (primary outcome) and physical function and depression (secondary outcomes). Results: 290 participants were enrolled (70.7% of whom were women, 66.9% minority group members, 72.4% at or below the poverty level, and 35.8% reading below the fifth grade level); 241 (83.1%) participated in posttreatment assessments. Linear mixed models included all randomly assigned participants. Members of the CBT and EDU groups had larger decreases in pain intensity scores between baseline and posttreatment than participants receiving usual care (estimated differences in change scores-CBT: -0.80 [95% CI -1.48 to -0.11]; P = 0.022; EDU: -0.57 [CI, -1.04 to -0.10]; P = 0.018). At 6-month follow-up, treatment gains were not maintained in the CBT group but were still present in the EDU group. With regard to physical function, participants in the CBT and EDU interventions had greater posttreatment improvement than those receiving usual care, and this progress was maintained at 6-month follow-up. Changes in depression (secondary outcome) did not differ between either the CBT or EDU group and the usual care group. Limitations: Participants represented a single health care system. Self-selection bias may have been present. Conclusion: Simplified group CBT and EDU interventions delivered at low-income clinics significantly improved pain and physical function compared with usual care. Primary Funding Source: Patient-Centered Outcomes Research Institute.

Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.

Multi-Elements in Waters and Sediments of Shallow Lakes: Relationships with Water, Sediment, and Watershed Characteristics.

We measured concentrations of multiple elements, including rare earth elements, in waters and sediments of 38 shallow lakes of varying turbidity and macrophyte cover in the Prairie Parkland (PP) and Laurentian Mixed Forest (LMF) provinces of Minnesota. PP shallow lakes had higher element concentrations in waters and sediments compared to LMF sites. Redundancy analysis indicated that a combination of site- and watershed-scale features explained a large proportion of among-lake variability in element concentrations in lake water and sediments. Percent woodland cover in watersheds, turbidity, open water area, and macrophyte cover collectively explained 65.2 % of variation in element concentrations in lake waters. Sediment fraction smaller than 63 µm, percent woodland in watersheds, open water area, and sediment organic matter collectively explained 64.2 % of variation in element concentrations in lake sediments. In contrast to earlier work on shallow lakes, our results showed the extent to which multiple elements in shallow lake waters and sediments were influenced by a combination of variables including sediment characteristics, lake morphology, and percent land cover in watersheds. These results are informative because they help illustrate the extent of functional connectivity between shallow lakes and adjacent lands within these lake watersheds.

Macrophytes in shallow lakes: relationships with water, sediment and watershed characteristics.

We examined macrophyte-environment relationships in shallow lakes located within the Prairie Parkland and Laurentian Mixed Forest provinces of Minnesota. Environmental variables included land cover within lake watersheds, and within-lake, water and sediment characteristics. CCA indicated that sediment fraction smaller than 63 µm (f<63), open water area, turbidity, and percent woodland and agricultural cover in watersheds were significant environmental variables explaining 36.6% of variation in macrophyte cover. When Province was added to the analysis as a spatial covariate, these environmental variables explained 30.8% of the variation in macrophyte cover. CCA also indicated that pH, f<63, percent woodland cover in watersheds, open water area, emergent vegetation area, and organic matter content were significant environmental variables explaining 43.5% of the variation in macrophyte biomass. When Province was added to the analysis as a spatial covariate, these environmental variables explained 39.1% of the variation in macrophyte biomass. The f<63 was the most important environmental variable explaining variation for both measures of macrophyte abundance (cover and biomass) when Province was added as a spatial covariate to the models. Percent woodland in watersheds, turbidity, open water area, and Ca+Mg explained 34.5% of the variation in macrophyte community composition. Most species showed a negative relationship with turbidity and open water area except for Potamogeton richardsonii, Stuckenia pectinata, and filamentous algae. Our study further demonstrates the extent to which macrophyte abundance and community composition are related to site- and watershed-scale variables including lake morphology, water and sediment characteristics, and percent land cover of adjacent uplands.

Slow-Growing Large Irritation Fibroma of the Anterior Hard Palate: A Case Report Using Immunohistochemical Analysis.

Irritation fibromas are recognized as fibrous lesions, usually reactive hyperplasias; however, the mechanism of enlargement is unclear. This paper reports on an abnormally large irritation fibroma of extremely gradual growth. The immunohistochemical features (CD34, α-SMA, vimentin, Ki-67, and TGF-α) of this irritation fibroma are presented to distinguish reactive hyperplasia from other true fibrous neoplasm diseases. In the only previous study, it was reported that the expression of TGF-α might be associated with the development of oral fibromas. Therefore, we investigated the relationship between this exceptionally-large fibrous lesion of extremely slow growth and the immunohistochemical reactivity of TGF-α, finding that, in contrast to the previous study, TGF-α was not expressed. This is the first study to evaluate the enlargement mechanism of such a large irritation fibroma using the approach of immunohistochemical analysis, and it indicates that such analysis can help elucidate the diverse causes and enlargement mechanisms of irritation fibromas.

Treatment of hind limb ischemia using angiogenic peptide nanofibers.

For a proangiogenic therapy to be successful, it must promote the development of mature vasculature for rapid reperfusion of ischemic tissue. Whole growth factor, stem cell, and gene therapies have yet to achieve the clinical success needed to become FDA-approved revascularization therapies. Herein, we characterize a biodegradable peptide-based scaffold engineered to mimic VEGF and self-assemble into a nanofibrous, thixotropic hydrogel, SLanc. We found that this injectable hydrogel was rapidly infiltrated by host cells and could be degraded while promoting the generation of neovessels. In mice with induced hind limb ischemia, this synthetic peptide scaffold promoted angiogenesis and ischemic tissue recovery, as shown by Doppler-quantified limb perfusion and a treadmill endurance test. Thirteen-month-old mice showed significant recovery within 7 days of treatment. Biodistribution studies in healthy mice showed that the hydrogel is safe when administered intramuscularly, subcutaneously, or intravenously. These preclinical studies help establish the efficacy of this treatment for peripheral artery disease due to diminished microvascular perfusion, a necessary step before clinical translation. This peptide-based approach eliminates the need for cell transplantation or viral gene transfection (therapies currently being assessed in clinical trials) and could be a more effective regenerative medicine approach to microvascular tissue engineering.

Cloning and expression of a cDNA for the rat kappa-opioid receptor.

We cloned a cDNA for the rat kappa-opioid receptor from a rat thalamus cDNA library. The deduced amino acid sequence consists of 380 residues with features shared by members of the G protein-coupled receptor family. The specific binding of [3H]bremazocine to the membrane of COS-7 cells transfected with the cDNA was displaced by kappa-specific opioid ligands, but not by mu- and delta-specific ligands. Xenopus oocytes injected with the in vitro transcribed mRNA responded to opioid ligands with the same subtype specificity. Northern blot analysis demonstrated that kappa-opioid receptor mRNA is expressed in a regionally specific manner in rat brain.

DAMGO, a mu-opioid receptor selective agonist, distinguishes between mu- and delta-opioid receptors around their first extracellular loops.

The structural basis of mu-opioid receptor (OPR) for the specificity in its ligand binding was investigated using chimeric mu/delta-OPRs. Replacement of the region around the first extracellular loop of delta-OPR with the corresponding region of mu-OPR gave the resultant chimeric receptor the similar affinity to DAMGO compared with the native mu-OPR. The reciprocal replacement deprived the high affinity to DAMGO from mu-OPR. These results indicate that the difference(s) in the structure around the first extracellular loop is critical for DAMGO to distinguish between mu- and delta-OPRs. Furthermore, displacement studies revealed that this region is partly involved in the discrimination between mu- and delta-OPRs by other peptidic mu-selective ligands, such as dermorphin, morphiceptin and CTOP, but not by non-peptidic ligands, such as morphine and naloxone.

Molecular cloning and in situ hybridization histochemistry for rat mu-opioid receptor.

We cloned a cDNA for the rat mu-opioid receptor from a rat thalamus cDNA library. The deduced amino-acid sequence of rat mu-opioid receptor consists of 398 residues with the features shared by the members of the G-protein coupled receptor family, and is 59% and 60% identical with those of rat kappa-opioid and mouse delta-opioid receptors, respectively. Northern blot analysis showed that expression of mu-opioid receptor mRNA was intensive in the thalamus, striatum, hypothalamus and pons-medulla, moderate in the hippocampus and midbrain, and slight in the cerebral cortex and cerebellum. More detailed distribution of the mRNA in the rat brain was examined using the in situ hybridization technique. Intense expression of mu-opioid receptor mRNA was observed in the internal granular and glomerular layers of the olfactory bulb, caudate putamen, nucleus accumbens, medial septum, diagonal band, medial preoptic area, several nuclei of thalamus, amygdala, interpeduncular nucleus, medial raphe nucleus, inferior colliculus, parabrachial nucleus, locus coeruleus, nucleus solitary tract and ambiguus nucleus. Furthermore, mu-opioid receptor mRNA was moderately expressed in the hippocampus, globus pallidus, ventral pallidus, arcuate hypothalamic nucleus, supramammillary nucleus, superior colliculus, periacqueductal gray, and several nuclei of lower brain stem, including raphe magnus nucleus, reticular gigantocellular nucleus and lateral paragigantocellular nucleus.

A novel AMPA receptor antagonist, YM872, reduces infarct size after middle cerebral artery occlusion in rats.

The neuroprotective effect of YM872 ([2.3-dioxo-7-(1H-imidazol-1-yl) 6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]acetic acid monohydrate), a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist with improved water solubility, was examined in a rat focal cerebral ischemia model. Rats were subjected to permanent middle cerebral artery (MCA) occlusion using the intraluminal suture occlusion method for 24 h. YM872 was intravenously infused for 4 h (20 and 40 mg/kg/h) or 24 h (10 and 20 mg/kg/h), starting 5 min after the MCA occlusion, to investigate the effect of prolonged duration of the treatment on infarct volume. In the 4 h infusion study, YM872 reduced the cortical infarct volume by 48% at a dose of 40 mg/kg/h. YM872 did not significantly reduce the infarct at 20 mg/kg/h for 4 h. In the 24 h infusion study, however, YM872 markedly reduced the cortical infarct volume by 62%, even at 20 mg/kg/h. The present study indicates that the neuroprotective effect of YM872 is enhanced by extending the duration of treatment, and demonstrates the benefit of the prolonged treatment with AMPA antagonists following focal cerebral ischemia. YM872, a highly water soluble compound, is applicable to investigate the role of AMPA receptors in ischemic models without concern about nephrotoxicity and could be useful in the treatment of human stroke.

In situ hybridization study of mu- and kappa-opioid receptor mRNAs in the rat spinal cord and dorsal root ganglia.

Distributions of mu- and kappa-opioid receptor mRNAs in the lumbar spinal cord and dorsal root ganglia of the adult rat were examined using the in situ hybridization technique. In the lumbar spinal cord, mu-opioid receptor mRNA was expressed intensely in laminae I, II and VIII. On the other hand, kappa-opioid receptor mRNA was expressed intensely in laminae I and II, and moderately throughout laminae III-VIII. In the dorsal root ganglia, mu-opioid receptor mRNA was intensely expressed and kappa-opioid receptor mRNA was expressed in a smaller number of cells than mu-opioid receptor mRNA.

In situ hybridization study of kappa-opioid receptor mRNA in the rat brain.

Distribution of kappa-opioid receptor mRNA in rat brain was examined by in situ hybridization technique. kappa-Opioid receptor mRNA was expressed in various brain regions, especially intensely in the neocortex (layer V and VI), caudate-putamen, nucleus accumbens, preoptic area, paraventricular thalamic nucleus, amygdala, several nuclei of hypothalamus, ventral tegmental area and substantia nigra pars compacta.

Carcinogenicity of benzotrichloride administered to mice by gastric intubation.

Epidemiological studies suggest that benzotrichloride (BTC) is a human carcinogen. In the present study, BTC was tested to evaluate its ability to induce lung tumors as a result of systemic exposure. Administration of BTC by gastric intubation, 2.0-0.0315 microliters/mouse (4 doses), twice a week for 25 weeks, in female ICR mice, produced forestomach tumors (squamous cell carcinoma and papilloma), lung tumors (adenocarcinoma and adenoma) and tumors of the hematopoietic system (thymic lymphosarcoma and lymphatic leukemia) with dose-related response by 18 months. The present and previous studies indicate that the target organs of BTC carcinogenesis in mice are the local tissue which is primarily exposed, and the lung and hematopoietic tissue when BTC is administered systematically.

Lung lesions induced by intratracheal instillation of vanadium pentoxide powder in rats.

To clarify acute toxicity and histopathological changes in the lung after exposure to V2O5 powder, rats (SD, male, n=66) were observed for 4 weeks after an intratracheal administration of V2O5 powder (geometric mean diameter 0.31 microm, geomertic standard deviation sigmag=2.19) at three doses (0.88, 3.0, 13.0 mg/kg body weight). The histopathological lung lesions were developed dose-dependently, and characterized by exudative inflammation, injury of alveolar macrophages, and swelling and mucous degeneration in the broncho-bronchiolar epithelia. Growth rate of the V2O5 powder-instilled rat was also retarded dose-dependently. The V2O5 powder used was composed of not coagulated but well dispersed particles consisting of vanadium pentoxide of more than 99.8% (w/w) with vanadium tetraoxide of less than 0.2%. The V2O5 powder was found to be 8 times more soluble in an artificial biological fluid "Gamble's solution" than in a pure water. From the present findings as well as those from the related literature, it was inferred that the histopathological lesions induced by the intratracheally instilled V2O5 powder are caused not only by the V2O5 particles per se but also by vanadium ions dissolved from the particles into the lung fluid.

Lung lesions induced by intratracheal instillation of nickel fumes and nickeloxide powder in rats.

Acute and subacute lung toxicity of nickel fumes was examined by single and repeated intratracheal instillation of nickel fumes and Ni2O3 and NiO powders in the rat. LD50 of nickel fumes was estimated as 38.2 mg/kg body weight (b.w.) according to the method of Litchfield and Wilcoxon. Body weight gain was retarded as in the order of a single dose of 13.0 mg Ni2O3/kg > 14.3 mg nickel fumes/kg > 1.4 mg Ni2O3/kg > 13.0 mg NiO/kg b.w. compared to controls. The histopathological changes in the lungs of the 14.3 mg nickel fumes/kg-dosed rats were milder than those induced by administration of 13.0 mg Ni2O3/kg but severer than those induced by administration of 1.4 mg Ni2O3/kg b.w. A single administration of NiO powder did not produce any histopathological effects on the lungs. The repeated administration of nickel fumes produced persistent edema and proteinosis in the alveoli. The nickel fumes, which were chemically composed of 97% of NiO and 3% of Ni2O3, were very fine particles about 5-10 nm in diameter, partly aggregated into larger particles and spherical particles about 0.6 micron in diameter. Solubility in distilled water and saline was in the order of nickel fumes > Ni2O3 powder > > NiO powder. It was suggested that a toxic Ni2O3 component and very fine particles of nickel fumes are involved in the acute lung toxicity of nickel fumes. The epithelial injury induced by reactive oxygen and hydroxy radicals, which would be produced during the process of conversion of Ni(III) to Ni(II) and phagocytosis of nickel fumes by macrophages and polymorphonuclear cells, are presumed to be involved in the pathogenesis of nickel fumes-induced lung lesion.

Hexavalent chromium responsible for lung lesions induced by intratracheal instillation of chromium fumes in rats.

Lung toxicity of chromium fumes (Cr fumes) was examined by a single intratracheal instillation into rats of 10.6 mg and 21.3 mg Cr fumes/kg body weight and by repeated (3 times) instillations of 10.8 mg and 21.7 mg Cr fumes/kg. The pathological changes were compared with those induced by single administrations of 3.2 mg and 19.2 mg Na2CO3 solution-insoluble fraction of Cr fumes (Cr-Fr)/kg and 20.8 mg commercially available chromium (III) oxide powder (Cr (III) oxide)/kg. Single and repeated administrations of Cr fumes suppressed growth rate in a dose-dependent manner, but administrations of Cr-Fr and Cr (III) oxide did not. A single administration of Cr fumes produced granulomas in the entire airways and alveoli with progressive fibrotic changes, as well as severe mobilization and destruction of macrophages and foamy cells. Those histopathological changes were aggravated by the repeated administration of Cr fumes. On the other hand, single administrations of Cr-Fr and Cr (III) oxide produced no remarkable histopathological changes. Cr fumes were found to be composed of 73.5% chromium (III) oxide and 26.5% chromium (VI) oxide. The primary particles of Cr fumes and Cr-Fr were similar, 0.02 micron in size (sigma g: 1.25), and Cr (III) oxide particles were 0.30 micron in size (sigma g: 1.53), measured by analytical electron microscopy (ATEM). Diffuse clusters of the primary particles in Cr fumes were identified as Cr (VI) oxide. The present results suggested that the lung toxicity of Cr fumes was mainly caused by these Cr (VI) oxide (CrO3) particles in Cr fumes.

Development of an inhalation system of high melting point metal fumes and its use for exposure of rats to chromium and nickel fumes.

An experimental inhalation system was developed for fumes generated from powders of high melting point metals such as chromium, nickel, manganese and iron. The system consisted of a plasma flame metal sprayer as a fume generator, a granular bed type fume collector, a fluidized bed aerosol generator, an exposure and a control chamber of a horizontal-flow type and inhalant monitoring and controlling units. Performance of the chambers was ensured by a distribution test using flyash as a test aerosol. Using this system, rats were exposed to chromium fumes for one week or to nickel fumes for two months. The exposure concentrations of the chromium and nickel fumes were 1.85 +/- 0.55 mg/m3 and 0.51 +/- 0.15 mg/m3 (mean +/- SD), near the target levels of 2 mg/m3 and 0.5 mg/m3, respectively. The mass median aerodynamic diameter and the geometric standard deviation of the chromium fumes were 2.1 microns and 2.00, respectively. Those of the nickel fumes were 3.7 microns and 1.74, respectively. Species analysis of these fume particles revealed that 26.4% of the total chromium was hexavalent and the residue was trivalent and that 1-3% of the total nickel was nickel(III) and the residue was nickel(II). Inhaled-metal concentrations in the lungs showed steady increases with the exposure periods and were within the normal range of variation. On the basis of these results, it is concluded that this system is useful for long-term inhalation experiments using high melting point metal fumes.

A new model rat with acute bronchiolitis and its application to research on the toxicology of inhaled particulate matter.

The aim of the present study was to establish a useful animal model that simulates humans sensitive to inhaled particulate matter (PM). We have developed a new rat model of acute bronchiolitis (Br) by exposing animals to NiCl2 (Ni) aerosols for five days. Three days following the Ni exposure, the animals developed signs of tachypnea, mucous hypersecretion, and bronchiolar inflammation which seemed to progress quickly during the fourth to fifth day. They recovered from lesions after four weeks in clean air. To assess the sensitivity of the Br rats to inhaled particles, two kinds of PM of respirable size were tested with doses similar to or a little higher to the recommended threshold limit values (TLVs) for the working environment in Japan. Titanium dioxide (TiO2 = Ti) was chosen as an inert and insoluble particles and vanadium pentoxide (V2O5 = V), as a representative soluble and toxic airborne material. The Br rats exposed to either Ti or V were compared the pathological changes in the lungs and the clearance of particles to those in normal control or Br rats kept in clean air. The following significant differences were observed in Br rats: 1. delayed recovery from pre-existing lesions or exacerbated inflammation, 2. reductions in deposition and clearance rate of inhaled particles with the progress of lesions. The present results suggest that Br rats are more susceptible to inhaled particles than control rats. Therefore, concentrations of particulate matter lower than the TLVs for Japan, which have no harmful effects on normal lungs, may not always be safe in the case of pre-existing lung inflammation.

Cadmium and associated metals in soils and sediments of wetlands across the Northern Plains, USA.

Cadmium, present locally in naturally high concentrations in the Northern Plains of the United States, is of concern because of its toxicity, carcinogenic properties, and potential for trophic transfer. Reports of natural concentrations in soils are dominated by dryland soils with agricultural land uses, but much less is known about cadmium in wetlands. Four wetland categories - prairie potholes, shallow lakes, riparian wetlands, and river sediments - were sampled comprising more than 300 wetlands across four states, the majority in North Dakota. Cd, Zn, P, and other elements were analyzed by ICP-MS, in addition to pH and organic matter (as loss-on-ignition). The overall cadmium content was similar to the general concentrations in the area's soils, but distinct patterns occurred within categories. Cd in wetland soils is associated with underlying geology and hydrology, but also strongly with concentrations of P and Zn, suggesting a link with agricultural land use surrounding the wetlands.

Multi-element accumulation near Rumex crispus roots under wetland and dryland conditions.

Rumex crispus was grown under wet and dry conditions in two-chamber columns such that the roots were confined to one chamber by a 21 mum nylon mesh, thus creating a soil-root interface ('rhizoplane'). Element concentrations at 3 mm intervals below the 'rhizoplane' were measured. The hypothesis was that metals accumulate near plant roots more under wetland than dryland conditions. Patterns in element distribution were different between the treatments. Under dryland conditions Al, Ba, Cu, Cr, Fe, K, La, Mg, Na, Sr, V, Y and Zn accumulated in soil closest to the roots, above the 'rhizoplane' only. Under wetland conditions Al, Fe, Cr, K, V and Zn accumulated above as well as 3 mm below the 'rhizoplane' whereas La, Sr and Y accumulated 3 mm below the 'rhizoplane' only. Plants on average produced 1.5 times more biomass and element uptake was 2.5 times greater under wetland compared to dryland conditions.