Prevalence and risk factors associated with asymptomatic malaria among school children: repeated cross-sectional surveys of school children in two ecological zones in Ghana.

BACKGROUND: Asymptomatic Plasmodium infections significantly drive malaria transmission and impact control and elimination strategies, but are largely uncharacterized. We investigated the prevalence and risk factors of asymptomatic malaria infections to inform malaria control strategies in Ghana. METHOD: Five cross-sectional surveys were conducted at the end of the peak transmission season (August-September) on 4892 school children aged between 6 and 14 years in two distinct ecological settings in Ghana between 2013 and 2017. The study sites were Begoro (forest ecology) and Cape Coast (coastal ecology). The children were screened for malaria parasites by microscopic examination of Giemsa-stained thin and thick blood films. Hemoglobin levels were measured using the Hemocue HB analyzer. In addition, height was measured and the height-for-age z-scores estimated from the reference population defined by WHO to determine children who were stunted. Proportions of categorical and means of continuous variables were compared using Chi-square test and Student's t-test respectively, and multivariable logistic regression was done to assess risk factors associated with asymptomatic infections. RESULTS: The overall prevalence of asymptomatic malaria in the school children was higher in Begoro compared to Cape Coast (27% (95% CI: 17, 24%) vs. 24% (95% CI: 17, 24%), p value = 0.04). The study recorded three species of Plasmodium (Plasmodia falciparum, malariae, and ovale) in both sites. Plasmodium falciparum was the predominant species, accounting for about 85% of infections in both study sites. The asymptomatic school children were more likely to be anaemic (OR = 2.01, p value< 0.001) and stunted in growth (OR = 1.46, p value< 0.001). Males carried more asymptomatic infection than females (OR = 1.18, p value = 0.015). School children aged 12-14 years had more asymptomatic infections than those aged 6-8 years (OR = 1.28, p value = 0.005). CONCLUSION: There is a considerable burden of asymptomatic malaria in the two regions of Ghana, which is associated with males, older children, anaemia, and stunted growth in children, and may have implications for malaria control and elimination strategies in Ghana.

Embedded tin nanocrystals in silicon-an electrical characterization.

Tin nanocrystals embedded in a SiSn layer grown by molecular beam epitaxy on n-type Si are investigated by means of deep level transient spectroscopy. Two Sn related deep traps are observed, depending on the annealing temperature of the samples. A deep level at [Formula: see text] (Sn1) is observed for annealing temperatures up to [Formula: see text]C, whereas a level at [Formula: see text] (Sn2) appears for annealing temperatures above [Formula: see text]C. Scanning transmission electron microscopy shows the formation of Sn nanocrystals at [Formula: see text]C, which coincides with the appearance of Sn2. Sn1 is tentatively assigned to a Sn related precursor defect, which transforms upon annealing into either Sn nanocrystals or an interface defect located at the nanocrystal surface.

Effects of cognitive therapy versus interpersonal psychotherapy in patients with major depressive disorder: a systematic review of randomized clinical trials with meta-analyses and trial sequential analyses.

BACKGROUND: Major depressive disorder afflicts an estimated 17% of individuals during their lifetime at tremendous suffering and cost. Cognitive therapy and interpersonal psychotherapy are treatment options, but their effects have only been limitedly compared in systematic reviews. METHOD: Using Cochrane systematic review methodology we compared the benefits and harm of cognitive therapy versus interpersonal psychotherapy for major depressive disorder. Trials were identified by searching the Cochrane Library's CENTRAL, Medline via PubMed, EMBASE, Psychlit, PsycInfo, and Science Citation Index Expanded until February 2010. Continuous outcome measures were assessed by mean difference and dichotomous outcomes by odds ratio. We conducted trial sequential analysis to control for random errors. RESULTS: We included seven trials randomizing 741 participants. All trials had high risk of bias. Meta-analysis of the four trials reporting data at cessation of treatment on the Hamilton Rating Scale for Depression showed no significant difference between the two interventions [mean difference -1.02, 95% confidence interval (CI) -2.35 to 0.32]. Meta-analysis of the five trials reporting data at cessation of treatment on the Beck Depression Inventory showed comparable results (mean difference -1.29, 95% CI -2.73 to 0.14). Trial sequential analysis indicated that more data are needed to definitively settle the question of a differential effect. None of the included trial reported on adverse events. CONCLUSIONS: Randomized trials with low risk of bias and low risk of random errors are needed, although the effects of cognitive therapy and interpersonal psychotherapy do not seem to differ significantly regarding depressive symptoms. Future trials should report on adverse events.

beta-Arrestin 1 and 2 stabilize the angiotensin II type I receptor in distinct high-affinity conformations.

BACKGROUND AND PURPOSE: The angiotensin II type 1 (AT(1)) receptor belongs to family A of 7 transmembrane (7TM) receptors. The receptor has important roles in the cardiovascular system and is commonly used as a drug target in cardiovascular diseases. Interaction of 7TM receptors with G proteins or beta-arrestins often induces higher binding affinity for agonists. Here, we examined interactions between AT(1A) receptors and beta-arrestins to look for differences between the AT(1A) receptor interaction with beta-arrestin1 and beta-arrestin2. EXPERIMENTAL APPROACH: Ligand-induced interaction between AT(1A) receptors and beta-arrestins was measured by Bioluminescence Resonance Energy Transfer 2. AT(1A)-beta-arrestin1 and AT(1A)-beta-arrestin2 fusion proteins were cloned and tested for differences using immunocytochemistry, inositol phosphate hydrolysis and competition radioligand binding. KEY RESULTS: Bioluminescence Resonance Energy Transfer 2 analysis showed that beta-arrestin1 and 2 were recruited to AT(1A) receptors with similar ligand potencies and efficacies. The AT(1A)-beta-arrestin fusion proteins showed attenuated G protein signalling and increased agonist binding affinity, while antagonist affinity was unchanged. Importantly, larger agonist affinity shifts were observed for AT(1A)-beta-arrestin2 than for AT(1A)-beta-arrestin1. CONCLUSION AND IMPLICATIONS: beta-Arrestin1 and 2 are recruited to AT(1A) receptors with similar ligand pharmacology and stabilize AT(1A) receptors in distinct high-affinity conformations. However, beta-arrestin2 induces a receptor conformation with a higher agonist-binding affinity than beta-arrestin1. Thus, this study demonstrates that beta-arrestins interact with AT(1A) receptors in different ways and suggest that AT(1) receptor biased agonists with the ability to recruit either of the beta-arrestins selectively, would be possible to design.

Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels.

SUMMARY OBJECTIVES: Stimulation of arginine vasopressin 2 receptor (V2R) with arginine vasopressin (AVP) results in a rise in von Willebrand factor (VWF) and factor VIII plasma levels. We hypothesized that gain-of-function variations in the V2R gene (AVPR2) would lead to higher plasma levels of VWF and FVIII. METHODS AND RESULTS: We genotyped the control populations of two population-based studies for four AVPR2 variations: a-245c, G12E, L309L, and S331S. Rare alleles of a-245c, G12E, and S331S, which were in linkage disequilibrium, were associated with higher VWF propeptide, VWF and FVIII levels. The functionality of the G12E variant was studied in stably transfected MDCKII cells, expressing constructs of either 12G-V2R or 12E-V2R. Both V2R variants were fully glycosylated and expressed on the basolateral membrane. The binding affinity of V2R for AVP was increased three-fold in 12E-V2R-green fluorescent protein (GFP) cells, which is in accordance with increased levels of VWF propeptide associated with the 12E variant. The dissociation constant (K(D)) was 4.5 nm [95% confidence interval (CI) 3.6-5.4] for 12E-V2R-GFP and 16.5 nm (95% CI 10.1-22.9) for 12G-V2R-GFP. AVP-induced cAMP generation was enhanced in 12E-V2R-GFP cells. CONCLUSIONS: The 12E-V2R variant has increased binding affinity for AVP, resulting in increased signal transduction, and is associated with increased levels of VWF propeptide, VWF, and FVIII.

Threshold response of benthic macrofauna integrity to metal contamination in West Greenland.

Sediment metal chemistry and benthic infauna surveys have been conducted over 33 years following a BACI protocol in relation to submarine tailings deposition (STD) from a lead-zinc mine in a western Greenland fjord system. We found clear predictable changes of benthic fauna composition in response to STD both temporally and spatially. Faunal re-colonization 15 years after mine closure, was slow and the impacted areas were still dominated by opportunistic species, although the most opportunistic ones (e.g. Capitella species) had decreased in importance. Concentration-response relations between sediment lead and faunal indices of benthic community integrity (e.g. the AMBI and DKI indices) indicated a threshold of ca. 200mg/kg, above which deterioration of faunal communities occurred. Above this threshold, diversity decreased dramatically and dominance of sensitive and indifferent species was substituted by tolerant or opportunistic species. Disposal of metal contaminated tailings may have long lasting effects on the biological system.

Complete activation of Bax by a single site mutation.

Bax translocation from the cytosol to mitochondria culminates a key step by which this protein mediates cell death. Here, we identified two amino acids, L70 and D71, within the BH3 domain of Bax that play a critical role in regulating Bax's cytosolic vs mitochondrial distribution. Individual substitution of these amino acids with alanine resulted in Bax conformational change, oligomerization, localization to mitochondria and cell death. Further mutational analysis indicated that L70 interacts with T174, V177 and A178 of Bax's C-terminal hydrophobic segment, while the negative charge of D71 is required for maintaining Bax in its soluble monomeric state. In summary, we have identified a new regulatory site that controls Bax's subcellular distribution and activation.

[Visits to hospital emergency departments after restricted-admission changes at the Rigshospitalet]. / Skadestuehenvendelser i H:S efter aendringen af skadestuestrukturen på Rigshospitalet.

INTRODUCTION: The aim of this study was to describe changes in the use of accident and emergency departments in the Copenhagen Hospital Co-operation after restricted admittance to the accident and emergency department at a large Danish university hospital, Rigshospitalet (admittance only for patients transported by ambulance or presenting with a referral from a doctor). MATERIAL AND METHODS: A retrospective study compared the number of patients treated in two periods, 1.7.1998 to 30.6.1999 and 1.7.1999 to 30.6.2000. Additional patient data were collected for the periods 1.7.1998 to 31.12.1998 and 1.7.1999 to 31.12.1999. RESULTS: A 4% decrease was seen in the total number of patients treated at the accident and emergency departments. The decrease in the number of patients treated at the accident and emergency department at Rigshospitalet was 69%, whereas the accident and emergency department at Bispebjerg Hospital experienced a 53% rise. DISCUSSION: The study showed good compliance in the local population after the restricted admittance to an accident and emergency department at a large university hospital. An expected total fall in the number of patients treated at the accident and emergency departments in the Copenhagen Hospital Co-operation could not be documented.

Stability balloon for two-dimensional vortex ripple patterns.

Patterns of vortex ripples form when a sand bed is subjected to an oscillatory fluid flow. Here we describe experiments on the response of regular vortex ripple patterns to sudden changes of the driving amplitude a or frequency f. A sufficient decrease of f leads to a "freezing" of the pattern, while a sufficient increase of f leads to a supercritical secondary "pearling" instability. Sufficient changes in the amplitude a lead to subcritical secondary "doubling" and "bulging" instabilities. Our findings are summarized in a "stability balloon" for vortex ripple pattern formation.

Structure and low-temperature thermal relaxation of ion-implanted germanium.

The structure of implantation-induced damage in Ge has been investigated using high resolution extended X-ray absorption fine structure spectroscopy (EXAFS). EXAFS data analysis was performed with the Cumulant Method. For the crystalline-to-amorphous transformation, a progressive increase in bond-length was observed without the presence of an asymmetry in interatomic distance distribution (RDF). Beyond the amorphization threshold the RDF was dose dependent and asymmetric, where the bond-length and asymmetry increased as functions of ion dose. Such an effect was attributed to the formation of three- and five-fold coordinated atoms within the amorphous phase. Low-temperature thermal annealing resulted in structural relaxation of the amorphous phase as evidenced by a reduction in the centroid, asymmetry and width of the RDF, as consistent with a reduction in the fraction of non four-fold coordinated atoms. The results have been compared to other EXAFS studies of amorphous Ge, and it is suggested that the range of bond-lengths reported therein is related to the sample preparation method and state of relaxation.

Functional reconstitution of the angiotensin II type 2 receptor and G(i) activation.

On the basis of the patterns of conserved amino acid sequence, the angiotensin II type 2 (AT(2)) receptor belongs to the family of serpentine receptors, which relay signals from extracellular stimuli to heterotrimeric G proteins. However, the AT(2) receptor signal transduction mechanisms are poorly understood. We have measured AT(2)-triggered activation of purified heterotrimeric proteins in urea-extracted membranes from cultured COS-7 cells expressing the recombinant receptor. This procedure removes contaminating GTP-binding proteins without inactivating the serpentine receptor. Binding studies using [(125)I] angiotensin (Ang) II revealed a single binding site with a K(d)=0.45 and a capacity of 627 fmol/mg protein in the extracted membranes. The AT(2) receptor caused a rapid activation of alpha(i) and alpha(o) but not of alpha(q) and alpha(s), as measured by radioactive guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding. Activation required the presence of activated receptors, betagamma, and alpha subunits. As a first step aimed at developing an in vitro assay to examine AT(2) receptor pharmacology, we tested a battery of Ang II-related ligands for their ability to promote AT(1) or AT(2) receptor-catalyzed G(i) activation. Two proteolytic fragments of Ang II, Ang III and Ang1-7, also promoted activation of alpha(i) through the AT(2) receptor. Furthermore, we found that [Sar(1),Ala(8)]Ang II is an antagonist for both AT(1) and AT(2) receptors and that CPG42112 behaves as a partial agonist for the AT(2) receptor. In combination with previous observations, these results show that the AT(2) receptor is fully capable of activating G(i) and provides a new tool for exploring AT(2) receptor pharmacology and interactions with G-protein trimers.

Implications of physical symmetries in adaptive image classifiers.

It is demonstrated that rotational invariance and reflection symmetry of image classifiers lead to a reduction in the number of free parameters in the classifier. When used in adaptive detectors, e.g. neural networks, this may be used to decrease the number of training samples necessary to learn a given classification task, or to improve generalization of the neural network. Notably, the symmetrization of the detector does not compromise the ability to distinguish objects that break the symmetry.

Structure of the RNA-dependent RNA polymerase of poliovirus.

BACKGROUND: The central player in the replication of RNA viruses is the viral RNA-dependent RNA polymerase. The 53 kDa poliovirus polymerase, together with other viral and possibly host proteins, carries out viral RNA replication in the host cell cytoplasm. RNA-dependent RNA polymerases comprise a distinct category of polymerases that have limited sequence similarity to reverse transcriptases (RNA-dependent DNA polymerases) and perhaps also to DNA-dependent polymerases. Previously reported structures of RNA-dependent DNA polymerases, DNA-dependent DNA polymerases and a DNA-dependent RNA polymerase show that structural and evolutionary relationships exist between the different polymerase categories. RESULTS: We have determined the structure of the RNA-dependent RNA polymerase of poliovirus at 2.6 A resolution by X-ray crystallography. It has the same overall shape as other polymerases, commonly described by analogy to a right hand. The structures of the 'fingers' and 'thumb' subdomains of poliovirus polymerase differ from those of other polymerases, but the palm subdomain contains a core structure very similar to that of other polymerases. This conserved core structure is composed of four of the amino acid sequence motifs described for RNA-dependent polymerases. Structure-based alignments of these motifs has enabled us to modify and extend previous sequence and structural alignments so as to relate sequence conservation to function. Extensive regions of polymerase-polymerase interactions observed in the crystals suggest an unusual higher order structure that we believe is important for polymerase function. CONCLUSIONS: As a first example of a structure of an RNA-dependent RNA polymerase, the poliovirus polymerase structure provides for a better understanding of polymerase structure, function and evolution. In addition, it has yielded insights into an unusual higher order structure that may be critical for poliovirus polymerase function.

Regulation of the onset of meiosis in the developing testis.

Meiotic division begins the process of spermatogenic maturation leading to sperm formation. In contrast to the ovary, in which meiosis is initiated early in development, onset of meiosis in the testis is delayed until the time of puberty. An assay procedure was utilized to evaluate factors responsible for the activation and prevention of meiosis in the developing rabbit testis. Testicular specimens from postnatal rabbits at different ages were used to determine if meiosis-activating substance (MAS) activity and meiosis-preventing substance (MPS) activity could be demonstrated prior to the onset of spermatogenesis. An in vitro system in which undifferentiated gonads from 11.5 day old mouse fetuses are cultured in test and control media was employed. The findings indicate that MAS activity is associated with the onset of spermatogenesis and is also present shortly after birth. Activity of MPS is present throughout much of the prespermatogenic period, with a decline to reach low levels at the onset of spermatogenesis.

Design of an ultrasonic therapy system for breast cancer treatment.

This paper describes the design of a novel ultrasonic therapy system dedicated to the breast cancer treatment and the theoretical investigation of the heating characteristics of the system. The applicator is a cylinder comprised of a stack of rings. Each ring has up to 48 transducers mounted on the inside of the ring and directed towards the centre. The transducers operate in one of two frequency bands (1.8-2.8 MHz and 4.3-40.8 MHz), arranged alternately in each ring. During treatment the patient is positioned in prone position, with the breast immersed in water and surrounded by this array. This design was modelled and optimized by 3-D simulations for a variety of treatment conditions. The simulated results demonstrate that the system has an excellent capability to achieve and maintain a temperature distribution (41.5-44 degrees C) in a quadrant to a whole breast. Initial experiments using a single ring of transducers has been performed to verify the power deposition calculation.

Pilot study of local hyperthermia, radiation therapy, etanidazole, and cisplatin for advanced superficial tumours.

Five patients (six hyperthermia sites) with advanced superficial tumours were treated with combined etanidazole, cisplatin, local hyperthermia, and radiation therapy as part of a Phase I pilot study. Treatment was given once weekly and consisted of etanidazole 3 gm/m2 IV bolus, cisplatin 50 mg/m2 IV bolus, hyperthermia for 60 min with a target temperature of 43 degrees C, and radiation therapy 500 cGy/fraction (median total dose 3000 cGy) for a total of six weeks. Blood levels of etanidazole were taken during treatment at week 1 and week 4. Etanidazole drug exposure was calculated using the trapezoidal rule and expressed as the area under the curve (AUC) of plasma concentration x time. Five of six treatment sites had received prior irradiation. Prior chemotherapy had been given in three patients and tamoxifen therapy given in the other two patients. The median follow-up time is 34 months; 3/5 patients have died of disease. The most significant toxicity was grade I or II nausea and vomiting associated with 19/32 treatments (59%) and a second degree burn in 2/6 fields. None of the five patients experienced peripheral neuropathy, skin ulceration, or needed surgical repair. In addition, there was mild renal toxicity; pharmacokinetic analysis showed a 28-75% increase in the week 1 to week 4 AUC in three patients, all of whom had a decrease in creatinine clearance over the same time of 15-47%. This pilot study suggests this combined modality therapy can be delivered without major complications and that renal function, determined by creatinine clearance, affects clearance of etanidazole and alters the AUC. Therefore, monitoring renal function is important in patients receiving etanidazole in addition to other nephrotoxic agents such as cisplatin. The impact of etanidazole on the therapeutic index of hyperthermia, radiation therapy and cisplatin may be worth of study, especially since a positive interaction between these modalities is found in laboratory models.

Local hyperthermia, radiation therapy, and chemotherapy in patients with local-regional recurrence of breast carcinoma.

We retrospectively reviewed the response rate and the acute and long-term toxicity of combined treatment using radiation therapy, hyperthermia, and chemotherapy in 29 patients with locally or regionally recurrent or advanced adenocarcinoma of the breast who completed at least 4 of the 6 prescribed hyperthermia treatments as part of a Phase I-II trial. Thirty-nine separate hyperthermia treatment fields were evaluated. Cisplatin alone or cisplatin with etanidazole or bleomycin was delivered just prior to hyperthermia once weekly. Hyperthermia was delivered to a target minimum tumor temperature of 43 degrees C +/- 0.5 for 60 min. Following hyperthermia, a 400 cGy fraction of radiation was given. The radiation fraction size on other days was 200 cGy. Twenty-two fields had previously been irradiated and 17 fields had not. Prior chemotherapy had been given in 24 of 29 patients (83%) and hormonal therapy given in 21 (72%). The median follow-up time is 10 months; 16/29 patients (55%) have died of disease. The overall complete response rate for all fields was 53%. Response rate was not related to any clinical factor, radiation dose, microwave or ultrasound technique, type of chemotherapy, or tumor temperatures, but the number of patients in the study population was small. A statistically significant association between the likelihood of complications and the total radiation therapy dose (previous radiation and present radiation) was found. Persistent ulceration lasting greater than 1 month after completing treatment was seen in 67% of previously irradiated fields compared to 21% of fields that had not been previously treated (p = 0.015). Surgical wound repair was needed for 38% of fields with a history of prior irradiation versus 6% of those without prior treatment (p = 0.050). A statistically significant radiation therapy dose response was found for the likelihood of these complications. None of the hyperthermia temperature parameters studied correlated with an increased risk of complication. We conclude that the combination of radiation therapy, hyperthermia, and chemotherapy results in a high rate of complete response. However, in patients who have been treated with prior radiation therapy, this combination may be more locally toxic than treatment with hyperthermia and radiation therapy alone. The precise impact of chemotherapy on the therapeutic index of hyperthermia and radiation therapy remains to be determined in randomized clinical trials.

Rescue angioplasty during myocardial infarction has a beneficial effect on mortality: a tenable hypothesis.

HYPOTHESIS: Rescue percutaneous transluminal coronary angioplasty (PTCA) reduces mortality during myocardial infarction. OBJECTIVE: To determine if PTCA after failed thrombolytic therapy results in reduced mortality. DESIGN: Twenty-eight patients with a persistently occluded infarct artery following thrombolytic therapy more than 3 h after symptom onset were randomized to rescue PTCA (n = 16) or conservative treatment (n = 12) as part of a prospective randomized trial of reperfusion therapy during myocardial infarction in 184 patients. Hospital mortality was assessed in these groups as well as in the 177 patients with known infarct artery status after initial attempts at reperfusion. MAIN RESULTS: There was one death among the 16 patients in the rescue PTCA group versus four deaths in the 12 patients treated conservatively (P = 0.13). Moreover, the death in the rescue PTCA group occurred in one of three patients in whom the procedure failed. Mortality in the entire study group was 10.3% (19 of 184); 4.2% (six of 142) in patients in whom patency was achieved after thrombolysis and/or PTCA and 34.3% (12 of 35) in those in whom reperfusion was not achieved (P less than 0.001). In patients with anterior myocardial infarction, mortality was 6.7% (four of 60) in those with reperfusion and 47.1% (eight of 17) in those with a persistently occluded artery (P less than 0.001). In patients with inferior myocardial infarction, 2.4% (two of 82) with reperfusion and 22.2% (four of 18) with a persistently occluded artery died (P less than 0.01). CONCLUSIONS: Although the number of patients in the randomized groups was small, the trend toward a lower mortality after rescue PTCA supports the hypothesis that rescue PTCA may be beneficial. The mortality results in relation to presence or absence of reperfusion from the entire study population underscores the importance of achieving patency during myocardial infarction.