Pyrethroid resistance in the Sudan Savannah Region in Nigeria: a study of the resistance profile and resistance mechanism of Anopheles populations from Hadejia Town in Jigawa State

Insecticide-based control measures are key strategies against malaria vectors, and pyrethroid is the only recommended class of insecticide for public health use. The work aimed at determining the pyrethroid resistance in Anopheline mosquitoes and the frequency of the knockdown resistance (kdr) gene determinant. Larval samples were collected from two sites in Hadejia Town, Jigawa State in April 2020 and November/December 2020, and reared to adulthood in Bayero University Kano Biochemistry's insectary. Samples were identified by morphological and molecular techniques. Three to five-day-old adult mosquitoes were exposed to standard concentrations of 0.75% permethrin and 0.05% deltamethrin according to WHO criteria. Kdr mutations were investigated using PCR. Results of morphological identification showed an abundance (100%) of the Anopheles gambiae complex. However, molecular identification showed varying percentages of An. gambiae s.s (15% and 35%), An. coluzzii (80% and 45%), and An. arabiensis (5% and 20%) each for agricultural and industrial sites, respectively. The result also revealed relatively higher KT50 and KT50 in the agricultural site and was relatively higher with permethrin based on the KT50. Higher insecticide resistance of Anopheles mosquitoes observed in the agricultural site suggests that the practice may affect resistance development. The frequency of negative (homozygous) L1014F kdr mutation genotype was 70% in the resistant (alive) mosquito population and 50% in the susceptible (dead) mosquito population. The frequency of kdr mutation for agricultural and industrial sites was 35% and 15%, respectively. This finding suggests that the kdr gene determinant may not be the only mechanism involved in the resistance of the Anopheline mosquito to pyrethroid

Genomic analysis of human and mouse TCL1 loci reveals a complex of tightly clustered genes

TCL1 and TCL1b genes on human chromosome 14q23.1 are activated in T cell leukemias by translocations and inversions at 14q32.1, juxtaposing them to regulatory elements of T cell receptor genes. In this report we present the cloning, mapping, and expression analysis of the human and murine TCL1/Tcl1 locus. In addition to TCL1 and TCL1b, the human locus contains two additional genes, TCL1-neighboring genes (TNG) 1 and 2, encoding proteins of 141 and 110 aa, respectively. Both genes show no homology to any known genes, but their expression profiles are very similar to those of TCL1 and TCL1b. TNG1 and TNG2 also are activated in T cell leukemias with rearrangements at 14q32.1. To aid in the development of a mouse model we also have characterized the murine Tcl1 locus and found five genes homologous to human TCL1b. Tcl1b1- Tcl1b5 proteins range from 117 to 123 aa and are 65-80% similar, but they show only a 30-40% similarity to human TCL1b. All five mouse Tcl1b and murine Tcl1 mRNAs are abundant in mouse oocytes and two-cell embryos but rare in various adult tissues and lymphoid cell lines. These data suggest a similar or complementary function of these proteins in early embryogenesis

Deregulated expression of TCL1 causes T cell leukemia in mice

The TCL1 oncogene on human chromosome 14q32.1 is involved in the development of T cell leukemia in humans. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. The TCL1 oncogene is activated in these leukemias by juxtaposition to the α or β locus of the T cell receptor, caused by chromosomal translocations t(14:14)(q11:q32), t(7:14)(q35:q32), or by inversions inv(14)(q11:q32). To show that transcriptional alteration of TCL1 is causally involved in the generation of T cell neoplasia we have generated transgenic mice that carry the TCL1 gene under the transcriptional control of the p56(lck) promoter element. The lck-TCL1 transgenic mice developed mature T cell leukemias after a long latency period. Younger mice presented preleukemic T cell expansions expressing TCL1, and leukemias developed only at an older age. The phenotype of the murine leukemias is CD4-CD8+, in contrast to human leukemias, which are predominantly CD4+CD8-. These studies demonstrate that transcriptional activation of the TCL1 protooncogene can cause malignant transformation oft lymphocytes, indicating the role of TCL1 in the initiation of malignant transformation in T prolymphocytic leukemias and T chronic lymphocytic leukemias

Telomerase activity, apoptosis and cell cycle progression in ataxia telangiectasia lymphocytes expressing TCL1

Individuals affected by ataxia telangiectasia (AT) have a marked susceptibility to cancer. Ataxia telangiectasia cells, in addition to defects in cell cycle checkpoints, show dysfunction of apoptosis and of telomeres, which are both thought to have a role in the progression of malignancy. In 1-5% of patients with AT, clonal expansion of T lymphocytes carrying t(14;14) chromosomal translocation, deregulating TCL1 gene(s), has been described. While it is known that these cells can progress with time to a frank leukaemia, the molecular pathway leading to tumorigenesis has not yet been fully investigated. In this study, we compared AT clonal cells, representing 88% of the entire T lymphocytes (AT94-1) and expressing TCL1 oncogene (ATM- TCL1 +), cell cycle progression to T lymphocytes of AT patients without TCL1 expression (ATM- TCL1-) by analysing their spontaneous apoptosis rate, spontaneous telomerase activity and telomere instability. We show that in ATM- TCL1+ lymphocytes, apoptosis rate and cell cycle progression are restored back to a rate comparable with that observed in normal lymphocytes while telomere dysfunction is maintained. © 2003 Cancer Research UK

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia

The combination of cytotoxic treatment with strategies for immune activation represents an attractive strategy for tumour therapy. Following reduction of high tumour burden by effective cytotoxic agents, two major immune-stimulating approaches are being pursued. First, innate immunity can be activated by monoclonal antibodies triggering antibody-dependent cellular cytotoxicity. Second, tumour-specific T cell responses can be generated by immunization of patients with peptides derived from tumour antigens and infused in soluble form or loaded onto dendritic cells. The choice of cytotoxic agents for such combinatory regimens is crucial since most substances such as fludarabine are considered immunosuppressive while others such as cyclophosphamide can have immunostimulatory activity. We tested in this study whether fludarabine and/or cyclophosphamide, which represent a very effective treatment regimen for chronic lymphocytic leukaemia, would interfere with a therapeutic strategy of T cell activation. Analysis of peripheral blood samples from patients prior and during fludarabine/cyclophosphamide therapy revealed rapid and sustained reduction of tumour cells but also of CD4+ and CD8+ T cells. This correlated with a significant cytotoxic activity of fludarabine/cyclophosphamide on T cells in vitro. Unexpectedly, T cells surviving fludarabine/cyclophosphamide treatment in vitro had a more mature phenotype, while fludarabine-treated T cells were significantly more responsive to mitogenic stimulation than their untreated counterparts and showed a shift towards TH1 cytokine secretion. In conclusion, fludarabine/cyclophosphamide therapy though inducing significant and relevant T cell depletion seems to generate a micromilieu suitable for subsequent T cell activation

The Novel Deacetylase Inhibitor AR-42 Demonstrates Pre-Clinical Activity in B-Cell Malignancies In Vitro and In Vivo

While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies.In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC(50) (50% growth inhibitory concentration) of AR-42 is 0.61 microM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC(50) (concentration lethal to 50%) of AR-42 is 0.76 microM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity.Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies

focus groups in migration research a forum for public thinking

This chapter outlines how to use focus groups (FGs) in migration studies, considering this method a forum for "public thinking" and discussing controversial issues. Moreover, the use of FGs allows us to understand the process of creating consensus and dissent via interaction. The chapter is structured in five sections: the first one introduces what FGs are and why they are useful for migration research; the second focuses on how to build the groups and how to do comparative migration research with FGs; the third illustrates how to prepare and to facilitate group discussion, and how to ask questions and engage participants in collaborative migration research; the fourth introduces how to interpret discussions and how to analyse the everyday naturalization of nation, ethnicity and race; the final section discusses how to communicate FG results. Each section is devoted to a specific methodological issue and it includes at least one "box" with an example from European migration research

Оценка эффективности комплекса методов медицинской реабилитации пациентов с двигательной дисфункцией кисти вследствие острых нарушений мозгового кровообращения

МЕДИЦИНСКАЯ РЕАБИЛИТАЦИЯКИСТЬ РУКИКИСТЬПСИХОМОТОРНАЯ АКТИВНОСТЬДВИГАТЕЛЬНЫХ НАВЫКОВ РАССТРОЙСТВА /РЕАБИЛРЕАБИЛИТАЦИЯ /МЕТОДЫМОЗГОВОГО КРОВООБРАЩЕНИЯ РАССТРОЙСТВА /ОСЛ /РЕАБИЛЛЕЧЕБНАЯ ГИМНАСТИКАМЕЛКАЯ МОТОРИКАЦелью исследования являлось изучение эффективности комплекса медицинской реабилитации, разработанного на основе зеркальной визуальной обратной связи, элементов двигательной терапии индуцированным ограничением, метода тренировки двигательных навыков кисти с использованием латексных резинок и авторского метода тренировки мелких моторных навыков у пациентов с двигательной дисфункцией кисти вследствие острого нарушения мозгового кровообращения различной степени выраженности. В исследовании приняли участие 62 пациента, разделенные на 2 группы сравнения, сопоставимые по полу, возрасту, реабилитационному периоду и потенциалу. Для анализа результатов использовались методы оценки эффективности медицинской реабилитации пациентов с двигательной дисфункцией кисти, утвержденные министерством здравоохранения Республики Беларусь. По результатам исследования было выявлено межгрупповое различие в восстановлении мелкой моторики, показателей кистевой динамометрии, уровне самооценки пациентом утраты функции верхней конечности, степени выраженности тревожной и депрессивной симптоматики, проявляющееся в более качественном результате у пациентов клинической группы. Также выявлено преобладание увеличений показателей и при оценке качества жизни у респондентов, проходящих предложенный комплекс методов медицинской реабилитации над пациентами контрольной группы. Разработанный комплекс, в условиях применения в соответствии с алгоритмом, позволяет более качественно по сравнению с пациентами, проходящими стандартный курс медицинской реабилитации, восстановить двигательный навык, утраченный вследствие острого нарушения мозгового кровообращения, улучшить степень самообслуживания, качества жизни и приводит к снижению выраженности тревожно-депрессивной симптоматики.Objectives. To study the efficacy of the medical rehabilitation complex developed on the basis of mirror visual feedback, elements of constraint induced movement therapy, the method of hand motor skills’ training with the use of latex rubber bands and the author’s own method of fine motor skills training in patients with motor dysfunction of the hand caused by acute cerebral circulation of different severity degree. Material and methods. The study involved 62 patients, divided into 2 comparison groups, matched by sex, age, rehabilitation period, and potential. To analyze the results we used methods for assessing the effectiveness of medical rehabilitation of patients with motor dysfunction of the hand, which were approved by the Ministry of Health of the Republic of Belarus. Results. The study revealed an intergroup difference in restoring fine motor skills, hand dynamometry indices, the patient’s self-assessment of the upper limb function loss, the severity of anxiety and depression symptoms, which manifests itself in a better result in patients of the clinical group. The prevalence of the increased indicators was also revealed when assessing the life quality of respondents undergoing the proposed complex of medical rehabilitation methods over patients of the control group. Conclusions. The developed complex, in terms of application in accordance with the algorithm, allows more qualitatively compared with patients undergoing a standard course of medical rehabilitation, to restore the motor skill lost because of acute cerebral circulation disturbance, to improve the degree of self-care, quality of life and leads to a decrease in anxiety-depression symptoms