Chloroquine resistance reversal agents as promising antimalarial drugs

The development and spread of resistance to antimalarial drugs poses a severe and increasing public health threat. Failures of prophylaxis or treatment with quinolines, hydroxynaphthoquinones, sesquiterpene lactones, antifolate drugs and sulfamides are involved in a return malaria-related morbidity and mortality. Resistance is associated with a decrease in accumulation of drugs into the vacuole, which results from a reduced uptake of the drug, an increased efflux or a combination of both. A number of candidate genes in P. falciparum have been proposed to be involved in antimalarial resistance, each concerned in membrane transport. Weaker or stronger associations are seen in P. falciparum between the resistance to quinolines or artemisinin derivatives and codon changes in Pfmdr1, a gene which encodes Pgh-1, an ortholog of one of the P-glycoproteins expressed in multi-drug resistant human cancer cells (ABC transporter). Further analysis has revealed a new gene, Pfcrt, encoding a PfCRT protein, which resembles an anion channel. Codon changes found in the Pfcrt sequence in drug resistant isolates could facilitate the drug efflux through a putative channel. It has been proposed that the reversal of quinoline resistance by verapamil is due to hydrophobic binding to the mutated PfCRT protein. Several compounds have demonstrated in the past decade a promising capability to reverse the antimalarial drug resistance in vitro in parasite isolates, in animal models and in human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic and antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and anthracenic derivatives. Here we summarize the progress made in biochemical and genetic basis of antimalarial resistance, emphasizing the recent developments on drugs, which interfere with trans membrane proteins involved in drug efflux or uptake.     

Spatial variation of waterborne radon and temporal variation of radon in water at nine Maine schools

Nine elementary schools in Maine were examined to track the release of 222Rn and to determine the transfer coefficient from water into air. Water-use simulations were performed by running sinks and sprayers for 1 h in a kitchen. The 222Rn in air was measured over 24 h throughout the school. The subsequent release of 222Rn into the kitchen air was measured to be greater than the EPA action level of 0.15 Bq L-1 (4 pCi L-1), but negligible concentrations of 222Rn were found in adjacent classrooms. In two schools, more than 10 222Rn-in-air detectors were placed throughout the kitchen and showed a three-fold spatial concentration variation. During the hour-long simulations, the 222Rn in water concentration was measured periodically, and many of the schools showed an increase in the 222Rn concentration in water before remaining constant. These measured variations suggest that multiple detectors are needed to accurately measure waterborne 222Rn in air, and multiple delayed measurements of 222Rn dissolved in water are needed to obtain a representative groundwater sample.     

Role of chemotherapy in hormone-refractory prostate cancer. Old issues,recent advances and new perspectives

Prostate cancer that grows despite castrate levels of testosterone and that no longer responds to any form of hormonal manipulation and for which nonhormonal approaches are required, can be precisely defined as hormone-refractory prostate cancer (HRPC). Until recently, there has been no standard chemotherapeutic approach for HRPC. In this article recent advances in the treatment of HRPC using chemotherapeutic regimens are critically reviewed. We performed a MEDLINE search of the published reports from 1995 to 2002 including chemotherapy in the treatment of HRPC. We critically reviewed a total of 84 clinical trials, of which only 6 were phase III trials, most of the studies being phase II trials. Various chemotherapeutic agents have been used. To date, the major benefits of chemotherapy in the treatment of HRPC are palliative in nature, in terms of reduction of pain and use of analgesics and improvement of performance status, as followed in the most recent trials. There is a promising activity of new drug combinations, such as vinca alkaloids and taxanes in association with estramustine. Mitoxantrone, although with a limited activity, has been shown to provide improvement in pain and quality of life for the patients. Several studies suffer from methodological deficits, such as small number of patients, heterogeneity of enrolled groups or no definitive response criteria. Further phase III studies are necessary to better evaluate the efficacy of the different regimens.     

Rectum separation in patients with cervical cancer for treatment planning in primary chemo-radiation

ABSTRACT: Purpose To proof feasibility of hydrogel application in patients with advanced cervical cancer undergoing chemo-radiation in order to reduce rectal toxicity from external beam radiation as well as brachytherapy. MATERIAL AND METHODS: Under transrectal sonographic guidance five patients with proven cervical cancer underwent hydro gel (20 cc) instillation into the tip of rectovaginal septum adherent to posterior part of the visible cervical tumor. Five days after this procedure all patients underwent T2 weighted transversal and sagittal MRI for brachytherapy planning. MRI protocol included T2 weighted fast spin echo (FSE) imaging in sagittal, coronal and paraaxial orientation using an 1.5 Tesla MRI. Separation of anterior rectal wall and cervix was documented. RESULTS: Hydrogel application was uneventful in all patients and no toxicity was reported. Separation ranged from 7 to 26 mm in width (median 10 mm). The length of the separation varied between 18 and 38 mm (median 32 mm). In all patients displacement was seen in the posterior vaginal fornix, and/or at the deepest part of uterine cervix depending on the extension of the cul-de-sac in correlation to the posterior wall of the uterus. In patients with bulky tumor and/or deep (vaginal) extend of peritoneal cavity tumour was seen mainly cranial from the rectovaginal space and therefore above the hydrogeI application. Only in the extra-peritoneal (lower) part of the cervix a good separation could be achieved between the rectum and cervix. CONCLUSION: Hydrgel instillation in patients with cervial cancer undergoing chemoradiation is safe and feasible. Because of the loose tissue of the cul-de-sac and its intra- and extraperitoneal part, hydrogel instillation of 20 cc did not result in a sufficient separation of the cervix from anterior wall.     

Different applications for left ventricular mechanical support with the Impella Recover 100 microaxial blood pump.

The "Impella Recover 100" (IR100) is a new intravascular microaxial blood pump for use as short-term mechanical support for cases of acutely reduced left ventricular function. From September 2002 to April 2003, we used the IR100 to support 5 patients: 2 patients were bridged to heart transplant; 2 were being treated for fulminant acute myocarditis; and 1 for post-cardiotomy low-output syndrome. Only 1 patient with myocarditis died of septic shock, 2 had successful heart transplants; and the latter 2 were slowly weaned from the device and, at 3-month follow-up, showed moderate improvement of left ventricular (LV) function. Our initial experience with the IR100 as mechanical support for patients in cardiogenic shock of varying etiology has been positive, yielding good survival in a population of particularly compromised patients.     

Cystic lymphanagioma of the upper extremity: US and MRI correlation (2004:11b)

The authors described a very rare case of the cystic lymphangioma (CL) of the left upper extremity in a 12-year-old patient. The diagnosis was made by US and MRI and confirmed by histological examination of the resected specimen.     

The association between high risk of sleep apnea,comorbidities, and risk of COVID-19: a population-based international harmonized study

Sleep and Breathing - Obstructive sleep apnea (OSA) may increase the risk of severe COVID-19; however, the level of potential modulation has not yet been established. The objective of the study was...     

Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation

BACKGROUND: Previous studies have shown that inhaled heparin attenuated the airway responses to allergen, exercise, and AMP bronchial provocation, possibly through an inhibition of mast cell activation. OBJECTIVE: The aim of this study was to provide the evidence of in vivo inhibition of human mast cell activation by heparin in a noninvasive model. METHODS: Nine atopic and 6 nonatopic subjects received placebo and unfractionated heparin sodium (5000 IU/mL) 15 minutes before an AMP nasal provocation in a double-blind crossover study design. The nasal lavage was collected from these subjects before or 3, 5, 15, or 30 minutes after the AMP nasal challenge, and concentrations of histamine and tryptase in the nasal lavage were measured. RESULTS: AMP nasal provocation produced considerable sneezing and induced a transient increase in histamine and tryptase release, with peak values achieved at 3 to 5 minutes after the challenge in all atopic subjects. Compared with placebo, inhaled heparin significantly attenuated the release of histamine and tryptase induced by AMP challenge (P=.012 and.004, respectively). Moreover, the AMP-induced sneezing was also inhibited by pretreatment with heparin (P=.016). In nonatopic subjects, AMP did not induce a significant increase in histamine and tryptase release on placebo-treated or heparin-treated days. CONCLUSION: These data suggest that AMP nasal provocation and AMP bronchial provocation cause mast cell mediator release in a similar fashion. In addition, the data support the hypothesis that inhaled heparin plays a protective role against AMP provocation by inhibition of mast cell activation.     

Lujo viral hemorrhagic fever: considering diagnostic capacity and preparedness in the wake of recent Ebola and Zika virus outbreaks

Lujo virus is a novel Old World arenavirus identified in Southern Africa in 2008 as the cause of a viral hemorrhagic fever (VHF) characterized by nosocomial transmission with a high case fatality rate of 80% (4/5 cases). Whereas this outbreak was limited, the unprecedented Ebola virus disease outbreak in West Africa, and recent Zika virus disease epidemic in the Americas, has brought into acute focus the need for preparedness to respond to rare but potentially highly pathogenic outbreaks of zoonotic or arthropod‐borne viral infections. A key determinant for effective control of a VHF outbreak is the time between primary infection and diagnosis of the index case. Here, we review the Lujo VHF outbreak of 2008 and discuss how preparatory measures with respect to developing diagnostic capacity might be effectively embedded into existing national disease control networks, such as those for human immunodeficiency virus, tuberculosis, and malaria.