Determinants of delayed childhood cancer care in low- and middle-income countries: A systematic review

Early access to care is essential to improve survival rates for childhood cancer. This study evaluates the determinants of delays in childhood cancer care in low- and middle-income countries (LMICs) through a systematic review of the literature. We proposed a novel Three-Delay framework specific to childhood cancer in LMICs by summarizing 43 determinants and 24 risk factors of delayed cancer care from 95 studies. Traditional medicine, household income, lack of transportation, rural population, parental education, and travel distance influenced most domains of our framework. Our novel framework can be used as a policy tool toward improving cancer care and outcomes for children in LMICs.     

Characterization of the GBoV1 Capsid and Its Antibody Interactions

Human bocavirus 1 (HBoV1) has gained attention as a gene delivery vector with its ability to infect polarized human airway epithelia and 5.5 kb genome packaging capacity. Gorilla bocavirus 1 (GBoV1) VP3 shares 86% amino acid sequence identity with HBoV1 but has better transduction efficiency in several human cell types. Here, we report the capsid structure of GBoV1 determined to 2.76 Å resolution using cryo-electron microscopy (cryo-EM) and its interaction with mouse monoclonal antibodies (mAbs) and human sera. GBoV1 shares capsid surface morphologies with other parvoviruses, with a channel at the 5-fold symmetry axis, protrusions surrounding the 3-fold axis and a depression at the 2-fold axis. A 2/5-fold wall separates the 2-fold and 5-fold axes. Compared to HBoV1, differences are localized to the 3-fold protrusions. Consistently, native dot immunoblots and cryo-EM showed cross-reactivity and binding, respectively, by a 5-fold targeted HBoV1 mAb, 15C6. Surprisingly, recognition was observed for one out of three 3-fold targeted mAbs, 12C1, indicating some structural similarity at this region. In addition, GBoV1, tested against 40 human sera, showed the similar rates of seropositivity as HBoV1. Immunogenic reactivity against parvoviral vectors is a significant barrier to efficient gene delivery. This study is a step towards optimizing bocaparvovirus vectors with antibody escape properties.     

Volumetric tomography of fluorescent proteins through small animals in vivo

Volumetric detection and accurate quantification of fluorescent proteins in entire animals would greatly enhance our ability to monitor biological processes in vivo. Here we present a quantitative tomographic technique for visualization of superficial and deep-seated (>2-3 mm) fluorescent protein activity in vivo. We demonstrate noninvasive imaging of lung tumor progression in a murine model, as well as imaging of gene delivery using a herpes virus vector. This technology can significantly improve imaging capacity over the current state of the art and should find wide in vivo imaging applications in drug discovery, immunology, and cancer research.     

Betablocker in der Therapie der chronischen Herzinsuffizienz

Hintergrund: Die antiadrenerge Therapie mit Betablockern bei der chronischen Herzinsuffizienz hat sich nach 25 Jahren von einer Kontraindikation zu einer etablierten Behandlungsform additiv zu einer konventionellen Basistherapie mit Diuretikum, einem ACE-Hemmer (alternativ AT1-Antagonist) und optional Digitalis entwickelt. Pathophysiologie: Eine kompensatorische Überaktivierung des sympathischen Nervensystems bei chronischer Herzinsuffizienz resultiert in der Induktion verschiedener, für die Herzmuskelzelle letztlich deletärer biologischer Signale. Die Tatsache, dass diese Signale über adrenerge Rezeptoren vermittelt werden, stellt die pathophysiologische Grundlage für den Einsatz einer Betablockade bei Herzinsuffizienz dar. Therapeutische Empfehlungen nach Studienlage Die drei größten Betablockerinterventionsstudien (CIBIS II, MERIT-HF, COPERNIKUS) zeigten unter additiver Gabe von Bisoprolol, Metoprolol bzw. Carvedilol einen eindeutigen Überlebensvorteil für die mit diesen Betablockern behandelten Patienten. Nach heutiger Datenlage sollten alle Patienten mit stabiler chronischer Herzinsuffizienz (NYHA II-IV) und nachgewiesener linksventrikulärer Funktionsstörung (LVEF < 45%) einen der drei genannten Betablocker erhalten. Eine Betablockertherapie sollte grundsätzlich nur bei stabilen Patienten additiv zu einem ACE-Hemmer und einem Diuretikum mit einer sehr niedrigen Dosis begonnen und langsam über mehrere Wochen bis zur maximal vom Patienten tolerierten Dosis auftitriert werden ("start low, go slow but high"). Der Erfolg der "paradoxen Intervention" stellt sich erst nach etwa 2-3 Monaten ein. Background: Once contraindicated, beta-blockers have become an established, evidence-based, recommended treatment concept in chronic heart failure during the last years. Pathophysiology: The increased activation of the adrenergic system in heart failure syndrome, which leads to transmission of several adverse biological signals to myocytes through adrenergic receptors, provides the rationale for the use of beta-blockers in patients with chronic heart failure. Long-term treatment with different types of beta-blockers additive to an ACE-inhibitor and diuretics results in normalization of left ventricular shape, an improvement of left ventricular function, and a reduction of hospitalization rate for heart failure. Hemodynamic and clinical improvement is independent of etiology and severity of left ventricular dysfunction. Therapeutical Recommendations Accordings to Studies: Adequately powered clinical trials (CIBIS II, MERIT-HF, COPERNIcUS) testing different types of beta-blockers (bisoprolol, metoprolol, carvedilol) clearly demonstrated that total mortality and the incidence of sudden cardiac death were significantly reduced in heart failure patients by each of these agents. On the basis of all available evidence, all patients with chronic, stable heart failure (NYHA class II-IV) and with impaired left ventricular function (LVEF < 45%) should receive one of the three above mentioned beta-blockers. Protective effects of beta-blockers in heart failure comprise decrease in heart rate, a decrease of energy consumption, antifibrillatory effects, protection against adrenergic overactivation, and hence, inhibition of myocardial cell necrosis. Moreover, several beta-blockers induce an up-regulation of beta-receptors leading to an improvement of contractility during long-term treatment. It should be mentioned that even a low dosage of beta-blockers exert negative inotropic effects and may lead to a deterioration of hemodynamics and heart failure symptoms in patients with heart failure. The patients treated should be informed that the success of the "paradoxical intervention" will be obvious until 2-3 months after initiation of additional beta-blocker therapy. Beta-blocker treatment for heart failure should be started in stable patients with a very low initial dosage and then up-titrated to the maximal tolerated dosage and should be continued indefinitely. Mortality reduction by beta-blockade in heart failure is no class effect. So far, beneficial effects could only be demonstrated for lipophilic agents. Whether the non-selective beta-blocker carvedilol with additional properties has advantages over the beta-1-selective metoprolol is currently investigated in the COMET (Carvedilol or Metoprolol European Trial) study. Despite the impressive effects in terms of morbidity and mortality reduction, the transfer of these benefits to the clinical practice setting is difficult, with international data showing only 10% of patients with heart failure being treated.     

Primary structure of a key enzyme in plant tetrapyrrole synthesis: glutamate 1-semialdehyde aminotransferase.

The formation of delta-aminolevulinate from glutamate 1-semialdehyde (GSA) is catalyzed by glutamate 1-semialdehyde aminotransferase (EC 5.4.3.8). The active form of the barley enzyme appears to be a dimer of identical subunits with a molecular mass of 46 kDa. From the purified enzyme, amino acid sequences of the N-terminal ends of the mature protein as well as an internal peptide were determined. DNA primers deduced from these peptide sequences were used to amplify with the polymerase chain reaction a cDNA sequence encoding part of the enzyme. Screening a cDNA library with this DNA fragment identified a full-length clone encoding the 49,540-Da precursor of the GSA aminotransferase. The transit peptide for chloroplast import consists of 34 amino acids. GSA aminotransferase and a precursor form were expressed on a multicopy plasmid in Escherichia coli. Both recombinant gene products reacted with an antibody against the barley GSA aminotransferase. Active barley GSA aminotransferase expressed in E. coli was shown to be active in assays of bacterial cell extracts. As a gene symbol for barley GSA aminotransferase, Gsa is proposed.     

Baseline Characteristics of Participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

-Diuretics and ss-blockers have been shown to reduce the risk of cardiovascular morbidity and mortality in people with hypertension in long-term clinical trials. No study has compared newer more costly antihypertensive agents (calcium antagonists, ACE inhibitors, and alpha-adrenergic blockers) with diuretics for reducing the incidence of cardiovascular disease in an ethnically diverse group of middle-aged and elderly hypertensive patients. The study is a randomized, double-blind, active-controlled clinical trial designed to determine whether the incidence of the primary outcome, fatal coronary heart disease or nonfatal myocardial infarction, differs between treatment initiation with a diuretic versus each of 3 other antihypertensive drugs. Men and women aged >/=55 years with at least 1 other cardiovascular disease risk factor were randomly assigned to chlorthalidone (12.5 to 25 mg/d), amlodipine (2.5 to 10 mg/d), lisinopril (10 to 40 mg/d), or doxazosin (2 to 8 mg/d) for planned follow-up of 4 to 8 years. This report describes the baseline characteristics of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants. A total of 42 448 participants were randomized from 625 sites in the United States, Canada, Puerto Rico, and the US Virgin Islands. The mean age was 67 years, with 35% aged >/=70 years. Among those randomized, 36% were black, 19% were Hispanic, and 47% were women. The sample includes a high proportion of people with diabetes (36%), patients with existing cardiovascular disease (47%), and smokers (22%). There were no important differences between the randomized treatment groups at baseline. ALLHAT will add greatly to our understanding of the management of hypertension by providing an answer to the following question: are newer antihypertensive agents similar, superior, or inferior to traditional treatment with diuretics?     

Placental Schistosoma haematobium infection in a German returnee from Malawi

Schistosomiasis is a widespread helminthic infection which sometimes may affect travelers to endemic areas. We report on a case of urogenital and placental schistosomiasis in a 28-year-old German woman who had been exposed to schistosomiasis in Lake Malawi one year earlier. She experienced painless macrohaematuria in her 21st week of pregnancy. Cystoscopy revealed vesical lesions typical for urogenital schistosomiasis. Histopathology confirmed ova of Schistosoma (S.) haematobium. The patient was treated with praziquantel 40 mg/kg/body weight/day for 3 days. After 285 days of gestation and 18 weeks post treatment, the patient delivered a healthy girl. Histopathology of placenta revealed eggs of S. haematobium in placental stroma. The infant proved negative for anti-Schistosoma spp. antibodies at the age of 15 months. This is the first report on placental schistosomiasis since 1980 and the first case occurring in a traveler.