Delay and attrition before treatment initiation among MDR-TB patients in five districts of Gujarat, India.

Setting: Gujarat, a state in west India. Background: Although treatment initiation has been improving among patients diagnosed with multidrug-resistant tuberculosis (MDR-TB) in programme settings, it has still not reached 100%. Objectives: To determine pre-treatment attrition (not initiated on treatment within 6 months of diagnosis), delay in treatment initiation (>7 days from diagnosis) and associated factors among MDR-TB patients diagnosed in 2014 in five selected districts served by two genotypic drug susceptibility testing (DST) facilities and a drug-resistant TB centre in Gujarat. Design: This was a retrospective cohort study involving record review. Results: Among 257 MDR-TB patients, pre-treatment attrition was seen in 20 (8%, 95%CI 5-12). Patients with 'follow-up sputum-positive' as their DST criterion and sputum smear microscopy status 'unknown' at the time of referral for DST were less likely to be initiated on treatment. The median delay to treatment initiation was 8 days (interquartile range 6-13). Patients referred for DST from medical colleges were more likely to face delays in treatment initiation. Conclusion: The Gujarat TB programme is performing well in initiating laboratory-confirmed MDR-TB patients on treatment. However, there is further scope for reducing delay.

Contexte : Dans le Gujarat, un état de l'ouest de l'Inde, même si la mise en route du traitement a été améliorée pour les patients ayant eu un diagnostic de tuberculose multirésistante (TB-MDR) dans le contexte des programmes, elle n'a pas encore atteint 100%.Objectif : Déterminer l'attrition avant traitement (c'est-à-dire un traitement pas mis en route dans les 6 mois suivant le diagnostic), le retard à la mise en route (>7 jours du diagnostic) et les facteurs associés parmi des patients TB-MDR diagnostiqués en 2014 dans cinq districts sélectionnés servis par deux structures de test génotypique de pharmacosensibilité (DST) et un centre de TB résistante au Gujarat.Schéma : Ceci a été une étude rétrospective de cohorte basée sur une revue de dossiers.Résultats : Sur 257 patients TB-MDR, l'attrition avant traitement a été constatée chez 20 patients (8% ; IC95% 5­12). Les patients ayant un « crachat de suivi positif ¼ comme critère de DST et un statut de microscopie de frottis de crachats « inconnu ¼ lors de la référence pour DST ont été moins susceptibles d'être mis sous traitement. Le délai médian de mise en route du traitement a été de 8 jours (intervalle interquartile 6­13). Les patients référés pour DST de centres hospitalières universitaires sont plus susceptibles de rencontrer des retards à la mise en route du traitement.Conclusion : Le programme TB du Gujarat est performant en mettant en route le traitement de TB-MDR confirmé par le laboratoire. Il reste cependant une marge d'amélioration en matière de réduction des délais.

Marco de referencia: Guyarat es un estado del occidente de la India donde se han logrado avances en la iniciación del tratamiento de los pacientes con diagnóstico de tuberculosis multirresistente (TB-MDR) en el marco programático, pero aún no se ha alcanzado el 100%.Objetivos: Determinar la tasa de abandono anterior al tratamiento (no haber iniciado tratamiento en un lapso de 6 meses después del diagnóstico), el retraso en la iniciación del tratamiento (>7 días después del diagnóstico) y los factores asociados en los pacientes diagnosticados con TB-MDR de cinco distritos escogidos de Guyarat atendidos por dos centros de pruebas genotípicas de sensibilidad a los medicamentos (DST) y un centro de tuberculosis resistente en el 2014.Método: Fue este un estudio de cohortes retrospectivo con examen de las historias clínicas.Resultados: De los 257 pacientes con diagnóstico de TB-MDR, se observó un abandono anterior al tratamiento en 20 casos (8%; IC95% 5­12). La probabilidad de iniciar el tratamiento era menor en los pacientes cuyo criterio para practicar las DST era 'seguimiento a la positividad del esputo' y su situación de la baciloscopia del esputo era desconocida en el momento de la remisión para las pruebas. La mediana del retraso en la iniciación del tratamiento fue 8 días (amplitud intercuartil 6­13). Los pacientes remitidos de las facultades de medicina para realizar las DST presentaban con mayor frecuencia retrasos en la iniciación del tratamiento.Conclusión: El desempeño del programa contra la TB de Guyarat es adecuado con respecto a la iniciación del tratamiento de los pacientes con TB-MDR confirmada por el laboratorio. Sin embargo, aún son necesarios progresos en esta esfera con el fin de acortar los retrasos.

Completion task to uncover consumer's perception: a case study using distinct types of hen's eggs.

The choice and consumption of eggs are made considering a consumers' multidimensional perception, and their understanding becomes essential to the production targeting and the products' success in the market. In this context, this work aimed to verify the consumers' perception about the distinct types of hens' eggs, using a projective technique of completion task combined with presentation of images. A hundred consumers (n = 100) evaluated the main factors, both positive and negative, involved at the purchase time of eggs besides estimating their price. Between the positive factors that guide the eggs' consumption and purchase, the category with highest mention of terms was "Health," whereas negatively it was highlighted the category "Price." Concerning the perception of price, the results showed that the factory farm white eggs' value was the one that least differed from the average market price, possibly due to the nearness and familiarity with this variety. The methodology of completion task combined with presentation of images proved as being a practical and efficient tool to capture the consumers' perception of eggs, capable of providing valuable information to the ones involved in the production chain and commercialization of these products.

Altitudinal flower size variation correlates with local pollinator size in a bumblebee-pollinated herb, Prunella vulgaris L. (Lamiaceae).

The influence of locally different species interactions on trait evolution is a focus of recent evolutionary studies. However, few studies have demonstrated that geographically different pollinator-mediated selection influences geographic variation in floral traits, especially across a narrow geographic range. Here, we hypothesized that floral size variation in the Japanese herb Prunella vulgaris L. (Lamiaceae) is affected by geographically different pollinator sizes reflecting different pollinator assemblages. To evaluate this hypothesis, we posed two questions. (1) Is there a positive correlation between floral length and the proboscis length of pollinators (bumblebees) across altitude in a mountain range? (2) Does the flower-pollinator size match influence female and male plant fitness? We found geographic variation in the assemblage of pollinators of P. vulgaris along an altitudinal gradient, and, as a consequence, the mean pollinator proboscis length also changed altitudinally. The floral corolla length of P. vulgaris also varied along an altitudinal gradient, and this variation strongly correlated with the local pollinator size but did not correlate with altitude itself. Furthermore, we found that the size match between the floral corolla length and bee proboscis length affected female and male plant fitness and the optimal size match (associated with peak fitness) was similar for the female and male fitness. Collectively, these results suggest that pollinator-mediated selection influences spatial variation in the size of P. vulgaris flowers at a fine spatial scale.

Reappraisal of the clinical significance of CD7 expression in association with cytogenetics in de novo acute myeloid leukaemia.

Debate exists over whether CD7 expression indicates an unfavourable prognosis in de novo acute myeloid leukaemia (AML). Meanwhile, the type of cytogenetics is a strong prognostic factor in AML. We analysed 256 de novo adult AML cases and found that the proportion of CD7+ cases increased stepwise from the cases with favourable cytogenetics to the cases with intermediate and unfavourable cytogenetics (3 out of 69 cases, 51 out of 140 cases and 25 out of 47 cases respectively, P < 0.0001). CD7-positivity adversely affected the survival only in the cases with unfavourable cytogenetics (P < 0.03). We recommend that CD7 expression in AML be interpreted in association with the cytogenetics.

Purification of proplatelet formation (PPF) stimulating factor: thrombin/antithrombin III complex stimulates PPF of megakaryocytes in vitro and platelet production in vivo.

In this study, the protein which stimulates proplatelet formation (PPF) of megakaryocytes was purified from normal human plasma using 7 steps procedures. Two different protease inhibitors were identified based on their amino acid sequences, i.e. antithrombin III (AT III) and C1 inhibitor. They were included in high density lipoprotein (HDL). HDL was necessary for AT III to be active in PPF in vitro. The biological effects of the AT III/HDL or thrombin-AT III (TAT)/HDL were studied in vitro. PPF of murine megakaryocytes was stimulated by negative control (BSA) (1.8 +/- 0.3%), AT III (2.0 +/- 0.4%), HDL (1.2 +/- 0.9%), AT III/HDL (14.8 +/- 2.1%) or TAT/HDL (23.3 +/- 3.5%), respectively. TAT/HDL also had a synergistic effect with the mpl ligand, judging by the acetylcholinesterase (AchE) expression of murine megakaryocytes (2.7 fold increase). In vivo subcutaneous administration of AT III alone or TAT for 3 days significantly stimulated thrombocytosis (136% and 144%, respectively, p<0.05) and AT III/HDL showed rapid and further stimulation (150%, p <0.01). These results and the previous studies indicate that megakaryocytopoiesis is regulated by the mpl ligand, while a protease/protease inhibitor complex such as TAT, which is involved in the coagulation cascade associated with platelet consumption, might be one of the regulators in platelet production.

Flow cytometric analysis of aberrant antigen expression of blasts using CD45 blast gating for minimal residual disease in acute leukemia and high-risk myelodysplastic syndrome.

To evaluate the availability of quantification of blasts with aberrant antigen expression (AAE) using CD45 gating for minimal residual disease (MRD), 15 patients with acute leukemia (AL) and myelodysplastic syndrome (MDS) were studied. In patients with complete remission (CR), the frequency of blasts with AAE (%AAE) by CD45/side scatter (SSC) gating was significantly higher than that by the traditional forward scatter (FSC)/SSC combination (median, 4.1 vs. 0.3%, P<0.0001). We also demonstrated two representative cases, in which leukemia relapse could be predicted before 3 weeks and the early treatment for MRD could be performed for MRD after allogeneic bone marrow transplantation (BMT). These results indicate that this procedure is very useful for the evaluation of the quality of CR.

[Autoimmune hemolytic anemia associated with adult-onset Still's disease].

A 37-year-old woman was admitted to our hospital in March 1995 because of high fever and cervical lymph node swelling. She had received prednisolone (PSL) therapy for autoimmune hemolytic anemia (AIHA). Laboratory examinations revealed increased serum levels of liver enzymes and C-reactive protein. Levels of rheumatoid factor and anti-nuclear antibody were within normal limits. On the basis of these criteria, she was diagnosed as having adult-onset Still's disease (AOSD). Although her fever ameliorated and physical symptoms disappeared immediately after a moderate dose of PSL, hemolysis recurred when attempts were made to reduce or withdraw the steroid. The patient is now receiving low-dose PSL therapy and is free of AIHA and AOSD.

Simple method for determination of the active metabolite of the inotropic drug pimobendan in rat liver microsomes.

A rapid and sensitive high-performance liquid chromatographic method for quantitation of the O-demethylated active metabolite formed in a liver microsomal assay system has been developed. The metabolite was separated on an Inertsil ODS-2 column and quantitated by fluorescence detection (excitation at 338 nm, emission at 405 nm). The retention times for pimobendan and its metabolite were 5.6 and 2.8 min, respectively. The intra- and inter-assay relative standard deviations in the measurement of pimobendan O-demethylase activity at the substrate concentrations of 1 microM and 500 microM were 2.0%, 6.8%, 2.1% and 5.6%, respectively, and the limit of detection was 0.1 ng for the demethylated metabolite.

Induction therapy consisting of alternating cycles of ranimustine, vincristine, melphalan, dexamethasone and interferon alpha (ROAD-IN) and a randomized comparison of interferon alpha maintenance in multiple myeloma: a co-operative study in Japan.

This pilot study evaluated the efficacy of a new combination chemotherapy with a newly developed nitrosourea derivative ranimustine and evaluated the efficacy of interferon alpha (IFN-alpha) maintenance in previously untreated patients with multiple myeloma (MM). The induction therapy (ROAD-IN) was a 6-week regimen consisting of chemotherapy with ranimustine, vincristine (Oncovin), melphalan (Alkeran) and dexamethasone starting on day 1 and IFN-alpha, which was administered three times weekly for 3 weeks starting on day 22. This was repeated for three cycles. The responders were subsequently randomized into two groups that received or did not receive IFN-alpha as maintenance therapy. Of the 164 patients registered, 161 were evaluated. An objective response to induction therapy was seen in 75% of patients; complete remission (CR) in 38 (24%) and partial remission (PR) in 82 (51%). The median survival for all patients was 3.6 years from registration. The survival of responders (CR + PR) was significantly better than that of non-responders (median survival 4.3 years vs. 1.4 years; 7-year survival rate 32% vs. 9%; P < 0.0001). The IFN-alpha maintenance did not show any advantage for either response duration or survival. This pilot study demonstrated that a comparatively short period of induction therapy with the ROAD-IN regimen produced a rather high response rate and a similar survival rate to those achieved with other longer induction regimens, and that good responders to the initial therapy survived significantly longer than non-responders.

Efficacy of a new formulation of lenograstim (recombinant glycosylated human granulocyte colony-stimulating factor) containing gelatin for the treatment of neutropenia after consolidation chemotherapy in patients with acute myeloid leukemia.

The efficacy and safety of a new formulation of lenograstim (recombinant glycosylated granulocyte colony-stimulating factor) prepared by switching the stabilizer from human serum albumin (HSA) to gelatin was investigated for the treatment of neutropenia after consolidation chemotherapy in patients with acute myeloid leukemia (AML). The results obtained in the study using the gelatin-containing formulation (gelatin-lenograstim) were retrospectively compared to those obtained from a placebo-controlled double-blind randomized study (AML-DBT) using the HSA-containing formulation (HSA-lenograstim). The median time of neutrophil recovery to > or = 1000/mm3 was significantly shorter in the gelatin-lenograstim group (14 days) than in the placebo group (21 days, P = .0001), and there was no significant difference between the gelatin-lenograstim group and the HSA-lenograstim group (14.5 days of AML-DBT, P = .5462). The incidences of febrile neutropenia were significantly reduced in the gelatin-lenograstim group (24/43, 55.8%) compared to the placebo group (58/64, 90.6%, P < .0001). The incidence of fever and antibiotic use was also significantly lower in the gelatin-lenograstim group (69.8% and 83.7%, respectively) than in the placebo group (92.2%, P = .0034, and 96.9%, P = .0285, respectively). However, between the 2 groups there were no differences in the number of patients who had infectious episodes. No serious adverse drug reactions ascribed to gelatin-lenograstim were encountered. These results demonstrate that gelatin-lenograstim exerted beneficial effects in the acceleration of neutrophil recovery and in the reduction of fever, febrile neutropenia, and antibiotic use, and its efficacy was equivalent to HSA-lenograstim. Therefore, we concluded that the gelatin-lenograstim formulation, which offers no risk of virus contamination and can be stored at room temperature, is more beneficial than the HSA-lenograstim formulation.

Identification of cytochrome P-450 isoform(s) responsible for the metabolism of pimobendan in human liver microsomes.

Pimobendan, 4, 5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)-5-methyl-3( 2-H )-pyridazinone, is a new inotropic drug that augments Ca(2+) sensitivity and inhibits phosphodiesterase in cardiomyocytes. Pimobendan is well absorbed after oral administration and is metabolized in the liver to the O-demethyl metabolite, which is also active. This study was conducted to identify the cytochrome P-450 (CYP) isoform(s) responsible for the pimobendan O-demethylation in human liver microsomes. Pimobendan O-demethylase activity in human liver microsomes was significantly correlated with phenacetin O-deethylase activity. CYP1A2 antibody and specific inhibitors of CYP1A2 strongly inhibited the metabolism of pimobendan. CYP1A2 was the only one of 10 recombinant human CYP isoforms tested that catalyzed pimobendan O-demethylation at the substrate concentration of 1 microM. At a high substrate concentration (100 microM), recombinant CYP3A4 also catalyzed the reaction, and antibody to CYP3A4 partially inhibited the activity in human liver microsomes. The contribution of CYP1A2 to pimobendan O-demethylation in human liver microsomes varied in the range of 18 to 76%, whereas CYP3A4 accounted for less than 10%, as calculated using the relative activity factor method. We conclude that CYP1A2 is one of the major enzymes responsible for the O-demethylation of pimobendan and CYP3A may make a minor contribution at clinically relevant concentrations of the drug.

Successful treatment of two patients with primary cardiac malignant lymphoma.

We describe two patients with primary cardiac malignant lymphoma involving the right atrium and superior vena cava, resulting in intractable right cardiac failure and superior vena cava syndrome. Patients were diagnosed by surgical myocardial biopsy and were treated with combination chemotherapy for non-Hodgkin's lymphoma. Each attained a marked response, and hence avoided sudden death from tricuspid atresia. Both have remained alive for more than 21 and 34 months, respectively, and continue intermittent combination chemotherapy.

Multiple red blood cell antibodies produced by donor B lymphocytes after ABO-matched allogeneic bone marrow transplantation.

A 50-year-old man with AML[M2,t(8;21)] underwent BMT from his younger sister. At that time, he had no unexpected antibody and his blood type was O(+), CcDEe. The type of Kidd was not examined. The donor's blood type was O(+), CCDee, Jk(a+b-). One year after the BMT, the patient's blood type had changed to that of the donor's and anti-E antibody was detected. Despite the use of platelet concentrates (PCs) only, anti-c antibody was later identified. We conclude that there is a need to check red cell antibodies at regular intervals, even when using PCs only, for earlier detection of unexpected antibodies after BMT.

[Blast crisis of chronic myelocytic leukemia that was difficult to differentiate from Ph+ acute lymphoblastic leukemia].

We encountered a 44-year-old woman with suspected chronic myelocytic leukemia (CML) in the acute phase that was difficult to be differentiate from Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). At disease onset, her bone marrow showed an increase in blasts that were negative for myeloperoxydase (MPO) and Positive for CD10, 19, 34, and HLA.DR. Standard type Ph was detected by chromosome analysis, and both major and minor BCR/ABL m-RNA were detected by reverse-transcriptase polymerase chain reaction (RT-PCR) methods. Neutrophil alkaliphosphatase (NAP) score was normal, and neither eosinophilia nor basophilia was observed in peripheral blood. Under a presumptive diagnosis of Ph-positive ALL (L2), the patient was given AdVP (doxorubicin, vincristine, and prednisolone) therapy followed by a regimen of LMVP (L-asparaginase, mitoxantrone, and VP), and obtained a complete remission 2 months later. At that time, FISH analyses of her bone marrow and blood cells no longer detected bone marrow Ph or BCR/ABL fusion gene. A month later, however, the leukemia relapsed with an increase in MPO-positive blasts in bone marrow, and the patient died soon thereafter. We finally concluded that her leukemia was not Ph-positive ALL, but CML in the acute phase at disease onset.