Copy Number Variations of Plasmodium vivax DBP1, EBP/DBP2, and RBP2b in Duffy-positive and Duffy-negative Ethiopians.

Recent evidence challenges the belief that Duffy-negative individuals are resistant to Plasmodium vivax due to lacking Duffy Antigen Receptor for Chemokines (DARC). Erythrocyte Binding Protein (EBP/DBP2) has shown moderate binding to Duffy-negative erythrocytes in vitro. Reticulocyte Binding Protein 2b (RBP2b) interactions with Transferrin Receptor 1 (TfR1) suggest involvement in Duffy-negative infections. Gene copy number variations (CNVs) in PvDBP1, PvEBP/DBP2, and PvRBP2b were investigated in Duffy-positive and Duffy-negative P. vivax-infected individuals from Ethiopia. Among Duffy-positive samples, 34% displayed PvDBP1 duplications (Cambodian-type). In Duffy-negative infections, 30% showed duplications, mostly Cambodian-type. For PvEBP/DBP2 and PvRBP2b, Duffy-positive samples exhibited higher duplication rates (1-8 copies for PvEBP/DBP2, 1-5 copies for PvRBP2b 46% and 43% respectively) compared to Duffy-negatives (20.8% and 26% respectively). The range of CNVs was lower in Duffy-negative infections. Demographic and clinical factors associated with gene multiplications in both Duffy types were explored, enhancing understanding of P. vivax evolution in Duffy-negative Africans.

Effects on cerebral blood flow after single doses of the ß2 agonist, clenbuterol, in healthy volunteers and patients with mild cognitive impairment or Parkinson's disease.

AIMS: Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic transmission from the locus coeruleus. In pre-clinical models, ß-adrenoceptor (ß-AR) agonists increase cerebrocortical glucose metabolism, and may have therapeutic potential for neurodegenerative diseases. This study investigated the safety and effects on regional cerebral blood flow (rCBF) of the oral, brain-penetrant ß2-AR agonist, clenbuterol, in healthy volunteers (HV) and patients with mild cognitive impairment (MCI) or Parkinson's disease (PD). METHODS: This study evaluated the safety and effects on cerebral activity of the oral, brain-penetrant, ß2-AR agonist clenbuterol (20-160 µg) in healthy volunteers and patients with MCI or PD. Regional CBF, which is tightly coupled to glucose metabolism, was measured by arterial spin labelling MRI in 32 subjects (25 HV and 8 MCI or PD) across five cohorts. In some cohorts, low doses of nadolol (1-5 mg), a ß-AR antagonist with minimal brain penetration, were administered with clenbuterol to control peripheral ß2-AR responses. RESULTS: Significant, dose-dependent increases in rCBF were seen in multiple brain regions, including hippocampus, amygdala and thalamus, following the administration of clenbuterol to HVs (mean changes from baseline in hippocampal rCBF of -1.7%, 7.3%, 22.9%, 28.4% 3 h after 20, 40, 80 and 160 µg clenbuterol, respectively). In patients with MCI or PD, increases in rCBF following 80 µg clenbuterol were observed both without and with 5 mg nadolol (in hippocampus, 18.6%/13.7% without/with nadolol). Clenbuterol was safe and well-tolerated in all subjects; known side effects of ß2-agonists, including increased heart rate and tremor, were mild in intensity and were blocked by low-dose nadolol. CONCLUSIONS: The effects of clenbuterol on rCBF were evident both in the absence and presence of low-dose nadolol, suggesting central nervous system (CNS) involvement. Concomitant inhibition of the peripheral effects of clenbuterol by nadolol confirms that meaningful ß2-AR antagonism in the periphery was achieved without interrupting the central effects of clenbuterol on rCBF.

Single- and Multiple-Dose Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist, in Healthy Adults.

Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials. Following single-dose administration of 10-450 mg, the pharmacokinetic (PK) profile of gefapixant in plasma and urine demonstrated low inter-subject variability and a dose-proportional exposure. Following administration of multiple doses twice daily, the plasma exposures were dose-proportional at doses ranging from 7.5 to 50 mg and less than dose-proportional at doses ranging from 100 to 1800 mg. The time to mean peak drug concentration ranged from 2 to 3 h post-dose, and steady state was achieved by 7 days after dosing, with an accumulation ratio of approximately 2, comparing data from day 1 to steady state. The mean apparent terminal half-life ranged from 8.2 to 9.6 h. Gefapixant was primarily excreted unmodified in urine. Gefapixant was well tolerated following single-dose administration up to 1800 mg and multiple doses up to 1800 mg twice daily; there were no serious adverse events (AEs) reported. The most common AE reported was dysgeusia. The PK profile supports a twice-daily dosing regimen.

Significado clínico y frecuencia de la alteración genético/molecular 11q23/MLL en lactantes con leucemia aguda en Chile / Clinical significance and frequency of the 11q23/MLL genetic/molecular alteration in chilean infants with acute leukemia

Background: Acute leukemia (AL) in infants generally shows distinctive biologic features and has a poor prognosis. Aim: To study the frequency of the cytogenetic alteration of11q23 chromosome or the recombination of MLL gene in infants less than 18 months old, with acute leukemia. Patients and methods: We analyzed 37 cases of AL in infants less than 18 months of age diagnosed in Chile from 1989 to 1999. The clinical features and cytogenetic/molecular defects of 11q23MLL gene rearrangement and their influence in prognosis were determined. Results: There were 18 cases of acute Lymphoblastic leukemia (ALL) characterized by female sex (67 per cent) high presenting leukocyte count (median 99 x109/L), blast cells with a CD10 negative phenotype (50 per cent) and 11q23/MLL rearrangement (39 per cent). Molecular abnormalities of 11q23 were significantly associated with adverse prognosis, with an event free survival (EFS) of only 14 ñ 12 per cent. Interestingly, infants with germ line 11q23 had a very good outcome with an EFS of 73 ñ 11 per cent (p<0.025). There were 19 cases of acute myeloblastic leukemia (AML) characterized by male sex (63 per cent) high leukocyte count (median 93 x 109/L), FAB-MS morphology (53 per cent) and 11q23/MLL rearrangement (53 per cent). EFS was very poor, 20 ñ 9 per cent and 33ñ4 per cent for rearranged and germinal group respectively (p=NS), due to a high mortality rate during the first month of diagnosis. Conclusions: These findings demonstrate that Chilean ALL infants with 11q23 abnormalities have a very poor prognosis. However those with germinal state can enjoy a prolonged disease free survival with the current treatment protocols

Leucemia linfoma T del adulto en Chile: estudio clínico patológico y molecular de 26 pacientes / Adult T cell leukemia lymphoma in Chile: a clinical-pathological and molecular study of 26 patients

Background: Adult T cell leukemia lymphoma is a lymphoproliferative syndrome etiologically associated to human T cell lymphotropic virus type I. Aim: To describe the clinical and laboratory features of 26 caucasian chilean patients, with HTLV-I positive adult T-cell leukemia lymphoma (ATLL). Material and methods: Diagnostic criteria included clinical features, cell morphology, immunophenotype, HTLV-I serology and/or DNA analysis by southern blot or PCR. Results: According to the clinical presentation, 12 cases had the acute ATLL form, 6 had a lymphoma, 4 the chronic form and 4 had smoldering ATLL. The median presentation age was 50 years, younger than the Japanese patients, but significantly older than patients from other south american countries (eg Brasil, Jamaica, Colombia). The main clinical features: lymphadenopathy, skin lesions and hepatosplenomegaly, were similar in frequency to those of patients from other countries, except for the high incidence of associated neurological disease. Tropical spastic paraparesis (TSP) in our series of ATLL, was seen in one third of the patients (8/26). A T-cell immunophenotype was shown in all 26 cases and HTLV-I serology was positive in 25/26 patients. Molecular analysis on the seronegative patient showed clonal integration of proviral HTLV-I DNA into the lymphocytes DNA, and thus he may have been a poor responder to the retroviral infection. Proviral DNA integration was also demonstrated in 15/16 patients being clonal in 10, polyclonal in 3 (all smoldering cases) and oligoclonal in one. Conclusions: ATLL in Chile has similar clinical and laboratory features than the disease in other parts of the world, except for a younger age than japanese patients but older than those from other latin american countries and a high incidence of patients with associated TSP. Detailed morphological and immunophenotypic analysis of the abnormal circulating lymphocytes, together with the documentation of HTLV-I by serology and/or DNA analysis are key tests for the identification of this disease