Particle size specific distribution of perfluoro alkyl substances in atmospheric particulate matter in Asian cities.

Seasonal and local characteristics of perfluorinated alkylated substances (PFASs) were examined using size-segregated particles including an ultrafine range. The examination included sampling and analysis of ambient particles collected at four sites located in different environments in three different countries, Japan (Kanazawa and Okinawa), Hong Kong and India. To minimize the evaporation artefacts derived from PFASs during the sampling, an air sampler that permitted particles smaller than 0.1 µm (PM0.1) to be separated at a moderate pressure drop (<5-15 kPa), was used for all of the air sampling procedures. In the case of Kanazawa, a local city in Japan, the concentration of PFASs was found to be dominated by carboxylates, especially PFOA, PFNA and PFDA regardless of the particle size and sampling period. Ultrafine particles were found to be the largest contributor to the mass fraction of PFCAs, while the maximum PFOS mass fractions were determined to be in the coarse-sized fractions. The seasonal difference in the total PFAS concentration can be largely attributed to precipitation. The results were basically similar for all sites that were examined. The type of land use may be a more influencing factor on the mass fraction of the PFASs than the country of origin. The dependency of PFAS mass fraction on the specific surface of the particle suggests that ultrafine PFAS particles are segregated, not only by gas deposition but could also be segregated by a mechanism involving compositional dependence or the primary source of the particles. Other possible sources of PFASs, other than from traffic are also possible.

Perfluoroalkyl substances in waters along the Grand Canal, China.

The Grand Canal, also known as the Beijing-Hangzhou Grand Canal, is a UNESCO World Heritage Site and the longest canal in the world. It is an important trunk line of the South-to-North Water Diversion Project in China. The contamination status and spatial distributions of perfluoroalky substances (PFASs) in waters of the Grand Canal were investigated. The total concentrations of PFASs (∑PFASs) range from 7.8 ng/L to 218.0 ng/L, with high ∑PFASs occurring in the southern part of the Grand Canal which is located in a highly urbanized and economically developed region. The dominance of PFOA showed a decreasing trend toward north while shorter chain homologue proportions increased in the northern part of the Canal which mainly traverses underdeveloped and rural areas in Eastern China. Positive correlations were observed between ∑PFASs and the population density as well as GDP per capita. Intersection with large rivers may affect the contamination levels and composition of PFASs in the water of the Grand Canal near the intersection sites.

Serum ferritin level is a prognostic marker in patients with peripheral T-cell lymphoma.

INTRODUCTION: The prognostic value of serum ferritin level in patients with peripheral T-cell lymphoma (PTCL) remains unknown. METHODS: We retrospectively analyzed clinical data from 78 consecutive patients with newly diagnosed PTCL that were treated with anthracycline-containing regimens between 1998 and 2011. RESULTS: The patients consisted of 50 males and 28 females with a median age of 64 years (range, 16-83 years). The subtypes of PTCL were 39 PTCL, not otherwise specified and 39 angioimmunoblastic T-cell lymphoma (AITL). The median observation period for the surviving patients was 50 months. The overall survival (OS) was poorer in patients with serum ferritin level above the upper normal limit (n = 28), compared with patients with serum ferritin level within normal range (n = 50; 4-year OS: 23% vs. 72%; P < 0.001). In the multivariate analysis, poor performance status (P = 0.006) and elevated serum ferritin level (P = 0.018) were independent risk factors for poor OS. CONCLUSION: Serum ferritin level is a useful prognostic marker for PTCL.

Clinical significance of pretransplant serum ferritin on the outcome of allogeneic hematopoietic SCT: a prospective cohort study by the Kanto Study Group for Cell Therapy.

This prospective study aimed to investigate the influence of pretransplant serum ferritin levels on the outcomes of allogeneic hematopoietic SCT (HSCT). In total, 190 patients with acute leukemia or myelodysplastic syndrome were consecutively enrolled. The patients were divided into two groups: low-ferritin group (<1000 ng/mL) and high-ferritin group (⩾1000 ng/mL). The primary end point was the cumulative incidence of infection within 100 days after HSCT, which was similar between the two groups: bloodstream infection, 35 vs 38%, P=0.65; bacterial infection, 44 vs 41%, P=0.68; and fungal infection, 6 vs 8%, P=0.71. The 1-year adjusted probability of OS of the high-ferritin group was significantly lower than that of the low-ferritin group (76 vs 63%, P=0.017). Using receiver operating characteristic curve, the threshold of pretransplant serum ferritin levels for bloodstream infection was 1400 ng/mL; the threshold for OS, EFS and non-relapse mortality was 1349 ng/mL. In conclusion, pretransplant serum ferritin levels of ⩾1000 ng/mL did not influence the incidence of infection but adversely affected OS after HSCT. A higher threshold of pretransplant serum ferritin levels may predict HSCT outcomes.

Characterization of a novel monoclonal antibody that senses nitric oxide-dependent activation of soluble guanylate cyclase.

Two monoclonal antibodies (mAbs) against bovine lung soluble guanylate cyclase (sGC) were prepared and characterized. mAb 3221 recognized both the alpha- and beta-subunits of sGC and had greater binding affinity to the enzyme in the presence of NO. mAb 28131 recognized only the beta-subunit and its affinity did not change with NO. Neither mAb cross-reacted with particulate GC. Cultured Purkinje cells from rats were treated with S-nitroso-N-acetylpenicillamine, an NO donor, and examined by immunocytochemical methods. The immunoreactivity associated with mAb 3221 increased with the cGMP content in a crude extract of cerebellum and the NO2 generated in the culture medium increased.

Autoantibody selectively inhibits binding of von Willebrand factor to glycoprotein ib. Recognition site is located in the A1 loop of von Willebrand factor.

A 20-year-old man with severe von Willebrand disease recently presented a progressive bleeding tendency, characterized recurrent subcutaneous hemorrhages and cerebral hemorrhage. Mixing and infusion studies suggested the presence of an inhibitor directed against vWF:RCo activity of von Willebrand factor (vWF) without significant inhibition of the FVIII:C. The inhibitor was identified as an antibody of IgG class. The inhibitor inhibited the interaction of vWF in the presence of ristocetin and that of asialo-vWF with GPIb while it partially blocked botrocetin-mediated interaction of vWF to GPIb. The inhibitor reacted with native vWF, the 39/34 kDa fragment (amino acids [aa] 480/ 481-718) and the recombinant vWF fragment (MalE-rvWF508-704), but not with Fragment III-T2 (heavy chains, aa 273-511; light chains, aa 674-728). A synthetic peptide (aa 514-542) did not inhibit vWF-inhibitor complex formation. We conclude that this is the first auto-antibody of class IgG from human origin that recognizes the sequence in the A1 loop of vWF, resulting in a virtual absence of functional vWF and a concomitant severe bleeding tendency although recognition site is different from the residues 514-542 which is crucial for vWF-GPIb interaction.

Induction of sister chromatid exchange in the presence of gadolinium-DTPA and its reduction by dimethyl sulfoxide.

RATIONALE AND OBJECTIVES: The authors investigate the frequency of sister chromatid exchange (SCE) after the addition of gadolinium (Gd)-DTPA to venous blood samples. METHODS: Venous blood was obtained from nonsmokers. Samples were incubated with Gd-DTPA alone or in combination with mitomycin C, cytarabine, and dimethyl sulfoxide (DMSO), and then evaluated for SCEs. RESULTS: The frequency of SCE increased with the concentration of Gd-DTPA and as each chemotherapeutic agent was added. Sister chromatid exchange frequencies were lower when the blood was treated with a combination of Gd-DTPA and DMSO compared with Gd-DTPA alone. DISCUSSION: The increase in frequency of SCE seen after the addition of Gd-DTPA was decreased by the addition of DMSO, indicating the production of hydroxyl radicals. The effect likely is dissociation-related.

Cold agglutinin disease following allogeneic bone marrow transplantation.

We describe a case of cold agglutinin disease (CAD) following allogeneic bone marrow transplantation. This 36-year-old male developed CAD 3 weeks after allogeneic bone marrow transplantation for chronic myelogenous leukemia. Cyclosporin A and methotrexate had been administered to prevent graft-versus-host disease. Other agents administered included cytomegalovirus hyperimmune globulin and recombinant human G-CSF. Pericarditis preceded the development of CAD. The characterization of cold agglutinin (CA) was monoclonal IgM-kappa with anti-Pr antigen specificity, probably derived from the engrafted donor lymphocytes. The administration of prednisolone led to transient improvement. The CA titer decreased without further treatment 12 weeks after transplant.

Thiotepa/cyclophosphamide/TBI as a conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome.

In all, 18 patients (30-56 years; median 49) with MDS underwent allogeneic HSCT from related (n=12) or unrelated (n=6) donors after a conditioning regimen comprising thiotepa, cyclophosphamide, and TBI. GVHD prophylaxis consisted of cyclosporine (n=15) or tacrolimus (n=3) with short-course methotrexate. Four patients had low-risk disease (refractory anemia or complete remission after chemotherapy) and 14 patients had high-risk disease (RAEB, RAEB-t, or AML). Grade II-IV acute GVHD developed in six patients and chronic GVHD in 10. With a median follow-up of 31 months, the 2-year survival probability is 75% for low-risk patients and 57% for high-risk patients. One patient died of leukemia and six of treatment-related causes. This conditioning regimen requires further study in patients with MDS.

Isolated extramedullary relapse in knee joint after allogeneic bone marrow transplantation for Ph ALL.

We report a patient who relapsed in a patella and knee joint after allogeneic bone marrow transplantation (BMT) for Ph chromosome-positive acute lymphoblastic leukemia. The patient complained of pain and swelling of knee joint 14 months post-BMT. Fluid from the knee joint included leukemic cells consistent with the immunophenotype of blasts prior to BMT and also revealed the bcr/abl transcript by reverse-transcriptase polymerase chain reaction. Magnetic resonance imaging demonstrated an abnormal signal in the patella. Radiotherapy to the localized extramedullary lesion was successful and no bone marrow relapse has been detected cytologically and cytogenetically to date. This case suggests that the physician should be aware of unusual relapse sites of leukemia post-BMT.

Diagnostic value of hemostatic parameters in bone marrow transplant-associated thrombotic microangiopathy.

We investigated hemostatic parameters in a prospective study of 16 patients who received bone marrow transplants (BMT). We found a significant rise in the levels of fibrinogen, plasmin-alpha2 antiplasmin inhibitor complex, tissue-plasminogen activator.plasminogen activator inhibitor complex (t-PA.PAI), von Willebrand factor antigen, and thrombomodulin on day 14 after transplant compared with values before transplant. Protein C and thrombin-antithrombin III levels did not change significantly. No significant changes in prothrombin time ratio, activated partial thromboplastin time, or protein S were detected. Patients who had grades II-IV graft-versus-host disease (GVHD) (n = 6) showed a significantly higher level of t-PA.PAI on day 14 compared with those with grades 0-I GVHD (n = 10) (P = 0.0062). Three patients with grades II-IV GVHD developed thrombotic microangiopathy (TMA) on days 19, 19 and 62. In these patients, we noted significantly lower levels of fibrinogen (P = 0.0383), and significantly higher levels of t-PA.PAI (P = 0.0008) and thrombomodulin (P = 0.0001) on day 14 compared with those patients who did not develop TMA. These results suggest that prothrombotic states and endothelial damage may be caused by the conditioning regimen and/or acute GVHD during BMT; thrombomodulin values on day 14 post BMT may be useful in surveillance for TMA because of endothelial cell injury.

The barrier function of the outer membrane of Pseudomonas maltophilia in the diffusion of saccharides and beta-lactam antibiotics.

This paper reports that the efficiency of solute diffusion through the outer membrane of Pseudomonas maltophilia is roughly 3 to 5% of that of Escherichia coli. This is despite the fact that the outer membrane pore(s) is only a little smaller than that of E. coli. These results suggest that P. maltophilia has a low copy number of porin(s). The outer membrane of antibiotic resistant clinical isolates showed even less efficient permeability towards saccharides and antibiotics than the laboratory strains.

Subcutaneous extramedullary hematopoiesis in a patient with secondary myelofibrosis following polycythemia vera.

We describe the case of a 73-year-old woman with secondary myelofibrosis who developed subcutaneous extramedullary hematopoiesis. Although extramedullary hematopoiesis has been generally observed in primary myelofibrosis, in this case it was seen in myelofibrosis secondary to polycythemia vera. Histological examination of the subcutaneous nodule revealed that the lesion included cells from the myeloid and megakaryocytic series. The skin lesion almost disappeared after treatment with hydroxyurea. We report here this rare manifestation in secondary myelofibrosis including a review of literature.

The effect of trihexyphenidyl, an anticholinergic agent, on regional cerebral blood flow and oxygen metabolism in patients with Parkinson's disease.

Cerebral blood flow and oxygen metabolism were studied in six previously untreated patients with Parkinson's disease (PD) before and after anticholinergic treatment using positron emission tomography (PET) and compared with six controls. The PET study and an assessment of the disability and cognitive impairment were performed before and after administration of 6 mg trihexyphenidyl for 5 to 11 weeks. All PD patients showed improvements in motor symptoms after the trihexyphenidyl treatment. Cognitive function did not significantly differ between before and after trihexyphenidyl treatment. However, after trihexyphenidyl treatment, rCBF and rCMRO2 decreased by 15% in the striatum and by 10% in all cortical areas contralateral to predominantly symptomatic limbs, and by 10% in the ipsilateral striatum and all cortical areas, significantly below the values of controls in most cerebral cortices and striatum. These findings suggest that trihexyphenidyl inhibits the cortical cholinergic system and significantly decreases rCBF and rCMRO2 in the cerebral cortices without cognitive impairment in untreated patients with PD.

Anomalous substituent effects in the bischler-napieralski reaction of 2-aryl aromatic formamides

Treatment of some 1-naphthylformamides (or formanilides) possessing a 2,4,5-trioxygenated phenyl substituent at the 2-position with POCl(3) caused an unprecedented carbon insertion reaction into a benzene ring, producing 7-5 ring (azaazulene) systems as valence isomers of isoquinoline skeletons. Precise examination of this abnormal Bischler-Napieralski reaction (BNR) using various substrates led to the following scope and limitations: (i) the 7-5 ring systems were constructed when either 2-alkoxy-4, 5-methylenedioxyphenyl- or 4,5-dialkoxy-2-hydroxyphenyl-substituted formamides were used as a starting substrate; (ii) in the former case the formyl carbon was inserted into the C(1)-C(6) bond of the 2-phenyl group, and normal isoquinoline cyclization competed with an abnormal carbon insertion reaction; (iii) the presence of a hydroxy group at the 2'-position as in the latter cases caused exclusive carbon insertion, in which alternative C(1)-C(2) insertion products were quantitatively formed; (iv) 3, 6-dimethoxy-2-hydroxyphenyl-substituted formanilide electronically equivalent to 4,5-dialkoxy-2-hydroxy derivatives produced an indole-pyrone as an abnormal BNR product. Theoretical approaches using the PM-3 method indicated that these abnormal BNRs could be triggered by ipso attack at the 1'-position yielding spiro intermediates. Ring cleavege of the six-membered ring in the spiro intermediates to a ketene function followed by recyclization was proposed for the 2'-hydroxy-directed abnormal BNRs leading to the C(1)-C(2) insertion product or the indole-pyrone derivative.

Variant of intron 22 inversions in the factor VIII gene in severe hemophilia A.

Recurrent DNA inversions, which disrupt the factor VIII (FVIII) gene, generally occur between a region of intron 22 (int22h) and one of two homologous copies of this region, located 300 to 400 kb telomeric to the FVIII gene. This report describes a patient with severe hemophilia A and a high level inhibitor with atypical hybridization patterns. A Bcl I Southern blot assay was altered to 17.5, 16, and 14 kb. His mother and two out of four aunts tested had normal and abnormal restriction patterns which led to a total of five different fragments, suggesting that they were carriers. The Xba I plus Kpn I restriction fragment-length polymorphism in intron 22 by Southern blotting using the same probe (probe a) yielded the 6.2 kb polymorphic band, with a clearly separated 6.6 kb band from the non-factor VIII region; an alternative int22h hybridization probe (probe x) detected no additional fragment. These results suggest that probe a as well as probe x could recognize an intron-22-sized fragment. This report shows a variation in the number of int22h copies although we could not find the inversion junction.

Chronic myelomonocytic leukemia with t(1;3)(p36;q21) and a synchronous gastric cancer.

The translocation t(1;3)(p36;q21) has been reported previously in patients with the myelodysplastic syndrome and with acute nonlymphocytic leukemia. It has been reported in only 5 cases of chronic myelomonocytic leukemia and t(1;3)(p36;q21). We observed a case of chronic myelomonocytic leukemia with t(1;3)(p36;q21) complicated by a gastric cancer at the time of diagnosis.

[A 52-week oral chronic toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187) in rats with a recovery period of 5 weeks.

The chronic toxicity of FUT-187, a synthetic protease inhibitor, was investigated in Sprague-Dawley rats. FUT-187 was given orally to the rats at doses of 0.4, 2, 10, 50 and 250 mg/kg/day for 52 weeks. The drug was then withdrawn for 5 weeks. The results are summarized as follows: There were no deaths or toxic signs caused by the drug throughout the experimental period. There were no drug-related changes in food consumption, ophthalmological examination, hematology or blood chemistry. Slight suppression of growth was observed in males in the 250 mg/kg group. This change was reversed on withdrawal of the drug. Drug crystals were observed in the urinary sediments of both sexes in the 250 mg/kg group, but this change disappeared on withdrawal of the drug. Gross pathological examination revealed the following changes: enlargement and nodule formation in the pancreas in both sexes given more than 10 mg/kg of the drug; dark red spots in the glandular stomach in males in the 250 mg/kg group; thickening of the small intestinal walls in both sexes given more than 50 mg/kg. Of these organs, no changes were observed in the stomach and small intestine at the end of the recovery period. Increased pancreas weight was observed in both sexes given more than 50 mg/kg of the drug. Examination at the end of the recovery period suggested reversibility, showing a lesser degree of change. Histopathological examination revealed the following changes in the pancreatic acinar cells: acidophilic foci and nodules in both sexes given more than 10 mg/kg of the drug; adenoma in one male in the 250 mg/kg group; increased zymogen granules in both sexes given more than 50 mg/kg of drug; fine vacuolization in females in the 250 mg/kg group. At the end of the recovery period, increased zymogen granules and fine vacuolization of the acinar cells were not found. Furthermore, erosion or healed erosion in the glandular stomach, duodenum and jejunum was observed in a few males or females in the 250 mg/kg group, but those changes disappeared after the recovery period. In the liver, altered cell foci was observed more frequently in males in the 250 mg/kg group than the other groups, but this change also disappeared after the recovery period. In addition, brown pigmentation in the proximal renal tubules of the kidney was observed in both sexes in the 250 mg/kg group, but lesions observed in the examination after the recovery period were less noticeable than in the examination at the end of the administration period.

[A 13-week subacute oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187) in rats].

The toxicity of FUT-187, a synthetic protease inhibitor, was investigated in Sprague-Dawley rats. FUT-187 was given orally to the rats at doses of 2, 10, 50, 250 and 1250 mg/kg/day for 13 weeks, then the drug was withdrawn for 5 weeks for recovery. The results are summarized as follows: In the 1250 mg/kg/day group, 9 out of 20 males died with decreased body weight and exhaustion. Histopathological examination revealed renal papillary necrosis, ulcer in the urinary bladder, hemostatic lesions in the lungs and liver, ulcer or erosion in the stomach, duodenum and jejunum. The surviving animals in this group showed swelling of the limbs due to synovitis, transient salivation immediately after administration, suppression of growth with decreased food consumption. Urinalysis revealed a low pH, increased ketones and bilirubin excretion, dark yellowish change in color, the appearance of "leaflet-shaped" crystals and increased red blood cells and epithelial cells in the urinary sediment, increased water intake, decreased specific gravity and decreased sodium, potassium and chloride in the urine. Hematologically, there was an increase in the white blood cell count. A biochemical analysis of the blood revealed decreased amylase activity, glucose and total protein levels and increased GOT activity and inorganic phosphorus levels. Pathological changes were observed in the pancreas, kidney, digestive tract, urinary bladder and liver. The pancreas showed macroscopical enlargement and increased organ weight. Histopathologically, there were several alterations in the acinar cells, such as vacuolization due to increased fat droplets, nuclear irregularity, prominent nucleoli, irregular arrangement and vesiculation of rough endoplasmic reticulum (rER), dilatation of developed Golgi apparatus and increased free ribosomes. In the kidney, increased weight and pigmentation in the proximal tubular epithelium were noted. Electron microscopically, these pigments were recognized as secondary lysosomes containing filamentous material and electron dense granules within a lucent matrix. In the digestive tract, ulcer or erosion in the stomach and duodenum, and villous proliferation in the small intestine were observed. Furthermore, hyperplasia and vacuolization were noted in the mucosal epithelium of the urinary bladder. In addition, loss of perilobular fat droplets in the liver and increased adrenal weight without histological change were observed. After a 5-week recovery period, these changes disappeared almost completely. In the 250 mg/kg/day group, slight suppression of growth the appearance of "leaflet-shaped" crystals in the urinary , sediment, increased water intake and decreased sodium in the urine were observed. The pancreas showed enlargement, increased weight, acinar cell hypertrophy with increased zymogen granules, fine vacuolization, slight derangement and vesicular of rER, and dilatation of Golgi apparatus.(ABSTRACT TRUNCATED AT 400 WORDS)