Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review.

CONTEXT In malaria-endemic regions, strategies to control malaria during pregnancy rely on case management of malaria illness and anemia, and preventive measures such as insecticide-treated nets and intermittent preventive therapy (IPT). OBJECTIVE To determine the effect of increasing resistance to sulfadoxine-pyrimethamine on the efficacy of IPT during pregnancy in Africa. DATA SOURCES AND STUDY SELECTION The 6 databases of MEDLINE, EMBASE, SCOPUS, LILACS, Cochrane CENTRAL, and the trial register and bibliographic database of the Malaria in Pregnancy Library were searched for relevant studies regardless of language, published between 1966 and December 2006. The reference lists of all trials identified were searched and researchers were contacted about relevant data. Nine trials of IPT with sulfadoxine-pyrimethamine during pregnancy in Africa were identified and matched by year and location with treatment studies of sulfadoxine-pyrimethamine among symptomatic children. DATA EXTRACTION Data on the efficacy of IPT with sulfadoxine-pyrimethamine on placental and peripheral malaria, birth weight, and hemoglobin level/anemia were independently abstracted by 2 investigators. Sulfadoxine-pyrimethamine resistance was defined as the proportion of total treatment failures in symptomatic children by day 14. DATA SYNTHESIS Four trials compared 2-dose IPT with sulfadoxine-pyrimethamine to case management or placebo in women during their first or second pregnancy. The IPT reduced placental malaria (relative risk [RR], 0.48; 95% CI, 0.35-0.68), low birth weight (RR, 0.71; 95% CI, 0.55-0.92), and anemia (RR, 0.90; 95% CI, 0.81-0.99). The effect did not vary by sulfadoxine-pyrimethamine resistance levels (range, 19%-26%). Efficacy of IPT with sulfadoxine-pyrimethamine was lower among women using insecticide-treated nets. Three trials compared 2-dose with monthly IPT with sulfadoxine-pyrimethamine during pregnancy. Among HIV-positive women in their first or second pregnancy, monthly IPT resulted in less placental malaria (RR, 0.34; 95% CI, 0.18-0.64) and higher birth weight (mean difference, 112 g; 95% CI, 19-205 g) over the range of sulfadoxine-pyrimethamine resistance tested (8%-39%). Among HIV-negative women, there was no conclusive additional effect of monthly dosing (2 trials; 24% and 39% resistance). CONCLUSIONS In areas in which 1 of 4 treatments with sulfadoxine-pyrimethamine fail in children by day 14, the 2-dose IPT with sulfadoxine-pyrimethamine regimen continues to provide substantial benefit to HIV-negative semi-immune pregnant women. However, more frequent dosing is required in HIV-positive women not using cotrimoxazole prophylaxis for opportunistic infections.
Spectrum of cyanotic congenital heart disease diagnosed by echocardiographic evaluation in patients attending paediatric cardiology clinic of a tertiary cardiac care centre

Abstract Background: Cyanotic CHD comprises up to 25% of cases of all causes of CHD. Rationale: There is lack of data about the present spectrum of congenital cyanotic heart disease in the paediatric age group. Objective: The present study was undertaken to determine the spectrum of patients with congenital cyanotic heart disease in the paediatric age group in tertiary paediatric cardiac care clinic. Design: Prospective observational study. Setting: Paediatric cardiac clinic of a tertiary cardiac care centre. Methods: All children aged 0–18 years with suspected cyanotic CHD were provisionally included in this study. They underwent a thorough echocardiographic evaluation, and those patients who had definitive diagnosis of congenital cyanotic heart disease were included for final analysis. Results: A total of 119 children met the inclusion criteria. Tetralogy of Fallot and its variant were the most common congenital cyanotic heart disease with proportion of about 44%. Other common malformations were double outlet right ventricle (14%), pulmonary atresia with ventricular septal defect (8%), total anomalous pulmonary venous connection (7%), d-transposition of the great arteries (9%), tricuspid valve anomalies − tricuspid atresia and Ebstein’s anomaly − hypoplastic left-heart syndrome, truncus arteriosus, and complex CHD such as single ventricle. Conclusion: Tetralogy of Fallot and its variants were the most common cyanotic heart disease diagnosed in our patients. As there were a significant proportion of cases with complex cyanotic CHD, paediatric cardiologists should be familiar with the diagnosis and management of all these complex congenital malformations of the heart.
Applying experiments to auctions in electricity markets

We analyze the bidding behavior in a single sided uniform auction and in a pay-as-bid auction using an experimental approach. This study focuses on the impact of the risk attitude of participating subjects. The experiments are conducted under a stable demand environment and with homogeneous groups consisting each of five participants either with a complete risk seeking or a complete risk averse attitude. The results show that a uniform auction is significantly affected by risk attitude of the participants. Standard deviation of efficiency and prices are higher when playing with risk averse participants. Compared to other existing literature on experimental economics, our results differ substantially and show that risk attitude of participants is a factor that needs to be taken into account especially when conducting experiments with small groups.
Impossible Mission: A History of the Legal Control of Native Drinking in Alaska

or as long as Alaskan Natives have been consuming alcohol, there have been attempts at social control of their drinking behavior. The use of alcohol by the Natives is linked to early trade relationships with Whites, and the establishment of commercial whaling, fishing, and mining. In the nineteenth century Russian traders brought guns, alcohol, and religion to the Natives. By the time Alaska was purchased from Russia in 1867, alcohol abuse was already in evidence, setting the stage for American social control, linked to education and religion, aimed exclusively at Native consumption. The consequences of alcohol abuse for Alaskan Natives are well known: high rates of suicide, homicide, and accidental deaths. Alcohol is closely associated with rural crime and it is the drug problem in Native villages. Special legislation for social control of Native drinking through prohibition or alcohol laws has had little effect. In this essay I o will explore the history of Native alcohol use and suggest reasons for the failure of alcohol control. 5 95
Strand-specific (asymmetric) contribution of phosphodiester linkages on RNA polymerase II transcriptional efficiency and fidelity

Significance The nonenzymatic RNA polymerization introduces backbone heterogeneity with a mixture of 2′–5′ and 3′–5′ linkages. RNA polymerase II (pol II) is a key modern enzyme responsible for synthesizing 3′–5′–linked RNA with high fidelity. It is unclear how pol II selectively recognizes the 3′–5′ over 2′–5′ linkage. Here, we systematically investigated how phosphodiester linkages of nucleic acids govern pol II transcriptional efficiency and fidelity. We revealed pol II has an asymmetric (strand-specific) recognition of phosphodiester linkage, which may reflect a universal principle of template-dependent genetic information transfer. Our results elucidate essential contributions of the phosphodiester linkage to pol II transcription and provide important understanding on nucleic acid recognition and genetic information transfer during molecular evolution. Nonenzymatic RNA polymerization in early life is likely to introduce backbone heterogeneity with a mixture of 2′–5′ and 3′–5′ linkages. On the other hand, modern nucleic acids are dominantly composed of 3′–5′ linkages. RNA polymerase II (pol II) is a key modern enzyme responsible for synthesizing 3′–5′–linked RNA with high fidelity. It is not clear how modern enzymes, such as pol II, selectively recognize 3′–5′ linkages over 2′–5′ linkages of nucleic acids. In this work, we systematically investigated how phosphodiester linkages of nucleic acids govern pol II transcriptional efficiency and fidelity. Through dissecting the impacts of 2′–5′ linkage mutants in the pol II catalytic site, we revealed that the presence of 2′–5′ linkage in RNA primer only modestly reduces pol II transcriptional efficiency without affecting pol II transcriptional fidelity. In sharp contrast, the presence of 2′–5′ linkage in DNA template leads to dramatic decreases in both transcriptional efficiency and fidelity. These distinct effects reveal that pol II has an asymmetric (strand-specific) recognition of phosphodiester linkage. Our results provided important insights into pol II transcriptional fidelity, suggesting essential contributions of phosphodiester linkage to pol II transcription. Finally, our results also provided important understanding on the molecular basis of nucleic acid recognition and genetic information transfer during molecular evolution. We suggest that the asymmetric recognition of phosphodiester linkage by modern nucleic acid enzymes likely stems from the distinct evolutionary pressures of template and primer strand in genetic information transfer during molecular evolution.
Differential distribution of 70-kD heat shock protein in atherosclerosis. Its potential role in arterial SMC survival.

Smooth muscle cell death may contribute to necrotic plaque rupture and subsequent thromboembolus. Stress-induced synthesis of heat-shock proteins (HSPs) normally protects cells from death, but vascular HSPs may become insufficient as cytotoxicity increases in advanced plaques. To determine whether vascular HSP content is altered near necrosis, we compared 70-kD HSP (HSP70) distribution between fibrotic and necrotic plagues in immunostained carotid endarterectomy specimens. Average levels of HSP70 immunoreactivity were compared by video densitometry between fibrotic and necrotic plaques or between their underlying media. Both necrotic plaques and their underlying media contained significantly more HSP70 staining than did fibrotic tissues. To test whether cellular HSP70 correlated with resistance to toxicity in vitro, aortic smooth muscle cells (aSMCs) were heat shocked to induce endogenous HSPs or given 2 to 50 micrograms/mL purified HSP70. Cells were then serum deprived or exposed to 12 to 96 mumol/L cholestanetriol (C3ol) or 25-hydroxycholesterol, and survival was determined. Cellular HSP70 content was assayed by immunoblotting, and protein synthesis was monitored by 35S radiolabeling. Serum deprivation inhibited general protein synthesis but induced HSP70; C3ol exposure inhibited both overall protein and HSP70 synthesis, including post-heat shock. Induction of endogenous HSPs or 10 micrograms/mL exogenous HSP70 improved viability of serum-deprived cells (P < .05 and P < .01, respectively), while only exogenous HSP70 protected against C3ol (P < .002). The results suggest that insufficient HSP70 accumulates in aSMCs residing near necrosis to protect against plaque toxicity; aSMC death might then occur, allowing resident macrophages to degrade and destabilize the matrix, leading to rupture.
Between Scylla and Charybdis: renegotiating resolution of the ‘obstetric dilemma’ in response to ecological change

Hominin evolution saw the emergence of two traits—bipedality and encephalization—that are fundamentally linked because the fetal head must pass through the maternal pelvis at birth, a scenario termed the ‘obstetric dilemma’. While adaptive explanations for bipedality and large brains address adult phenotype, it is brain and pelvic growth that are subject to the obstetric dilemma. Many contemporary populations experience substantial maternal and perinatal morbidity/mortality from obstructed labour, yet there is increasing recognition that the obstetric dilemma is not fixed and is affected by ecological change. Ecological trends may affect growth of the pelvis and offspring brain to different extents, while the two traits also differ by a generation in the timing of their exposure. Two key questions arise: how can the fit between the maternal pelvis and the offspring brain be ‘renegotiated’ as the environment changes, and what nutritional signals regulate this process? I argue that the potential for maternal size to change across generations precludes birthweight being under strong genetic influence. Instead, fetal growth tracks maternal phenotype, which buffers short-term ecological perturbations. Nevertheless, rapid changes in nutritional supply between generations can generate antagonistic influences on maternal and offspring traits, increasing the risk of obstructed labour.
Phase I trial of first-line bortezomib/thalidomide plus chemotherapy for induction and stem cell mobilization in patients with multiple myeloma.

BACKGROUND In preclinical studies, bortezomib was shown to suppress tumor growth, sensitize malignant cells to apoptosis, and reverse chemotherapy resistance. PATIENTS AND METHODS We evaluated the addition of escalating doses of bortezomib 0.7, 1, and 1.3 mg/m2 intravenously on days 1, 4, and 8 to DT-PACE (cisplatin 10 mg/m2, doxorubicin 10 mg/m2, cyclophosphamide 400 mg/m2, and etoposide 40 mg/m2 per day by intravenous continuous infusion on days 1-4) plus oral dexamethasone 40 mg on days 1-4 and thalidomide 200 mg on days 1-8 in newly diagnosed patients with multiple myeloma. Peripheral blood stem cells were collected after cycle 1. Twelve patients completed the study, and all received autologous stem cell transplantation (SCT). RESULTS Hematologic toxicities were predictable, with 3 episodes of neutropenic fever. Grade >/= 2 nonhematologic toxicities included diarrhea (n = 1), deep vein thrombosis (n = 2), hypotension (n = 2), syncope (n = 1), and peripheral neuropathy (n = 3). The median number of CD34+ cells collected was 20.57 x 10 superset6 CD34+ cells/kg. After 2 cycles, 10 of 12 patients exhibited a partial response or better. Best response after autologous SCT, complete response/near complete response was exhibited in 9 patients, and partial response was exhibited in 3 patients. At a median of 20 months, 4 patients experienced relapse and 1 had died. Bortezomib/DT-PACE compared favorably with DT-PACE with regard to leukapheresis days, total CD34+ cell collection, and engraftment. CONCLUSION This novel strategy of simultaneous proteasome inhibition in combination with thalidomide and chemotherapy was effective and safe, allowing for adequate stem cell collection and early autologous SCT; its impact on overall survival, especially in patients with high-risk myeloma, awaits further investigation.
Temporal changes in cardiorespiratory fitness and the incidence of hypertension in initially normotensive subjects

Low‐cardiorespiratory fitness (CRF) has been associated with incident hypertension, but whether temporal changes in CRF are associated with incident hypertension in initially normotensive subjects are not known. We investigated the relationship of baseline CRF and longitudinal changes in CRF with incident hypertension in initially normotensive subjects.
Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia.

PURPOSE Expression of Bcl-2 protein is associated with chemotherapy resistance and decreased survival in chronic lymphocytic leukemia (CLL). We evaluated whether oblimersen would improve response to chemotherapy in patients with relapsed or refractory CLL. PATIENTS AND METHODS Patients had received at least one prior fludarabine-containing regimen and were stratified on the basis of prior fludarabine response, number of prior regimens, and duration of response to last prior therapy. Patients were randomly assigned to 28-day cycles of fludarabine 25 mg/m2/d plus cyclophosphamide 250 mg/m2/d administered intravenously for 3 days with or without oblimersen 3 mg/kg/d as a 7-day continuous intravenous infusion (beginning 4 days before chemotherapy) for up to six cycles. The primary end point was the proportion of patients who achieved complete response (CR) or nodular partial response (nPR). RESULTS Of 241 patients randomly assigned, CR/nPR was achieved in 20 (17%) of 120 patients in the oblimersen group and eight (7%) of 121 patients in the chemotherapy-only group (P = .025). Achievement of CR/nPR was correlated with both an extended time to progression and survival (P < .0001). In patients who remained sensitive to fludarabine, oblimersen was associated with a four-fold increase in the CR/nPR rate and a significant survival benefit (P = .05). Oblimersen was frequently associated with thrombocytopenia and, rarely, tumor lysis syndrome and cytokine release reactions; the incidence of opportunistic infections and second malignancies was similar in both groups. CONCLUSION The addition of oblimersen to fludarabine plus cyclophosphamide significantly increases the CR/nPR rate in patients with relapsed or refractory CLL (particularly fludarabine-sensitive patients), as well as response duration among patients who achieve CR/nPR.
Prion Fibrillization Is Mediated by a Native Structural Element That Comprises Helices H2 and H3*

Aggregation and misfolding of the prion protein (PrP) are thought to be the cause of a family of lethal neurodegenerative diseases affecting humans and other animals. Although the structures of PrP from several species have been solved, still little is known about the mechanisms that lead to the misfolded species. Here, we show that the region of PrP comprising the hairpin formed by the helices H2 and H3 is a stable independently folded unit able to retain its secondary and tertiary structure also in the absence of the rest of the sequence. We also prove that the isolated H2H3 is highly fibrillogenic and forms amyloid fibers morphologically similar to those obtained for the full-length protein. Fibrillization of H2H3 but not of full-length PrP is concomitant with formation of aggregates. These observations suggest a “banana-peeling” mechanism for misfolding of PrP in which H2H3 is the aggregation seed that needs to be first exposed to promote conversion from a helical to a β-rich structure.
Leishmania/HIV co-infections: epidemiology in Europe

Abstract As the AIDS pandemic spreads to rural areas and human visceral leishmaniasis (VL) becomes more common in suburban areas, there is an ever greater degree of overlap between the geographical distributions of the two diseases and, in consequence, an increasing incidence of Leishmania/HIV co-infection. Cases of the co-infection have been reported from 35 countries around the world but most have been recorded in south-western Europe. There has been a total of 1911 cases detected in Spain, France, Italy and Portugal. The incidence of Leishmania/HIV co-infection is expected to continue increasing in eastern Africa but to fall in south-western Europe as increasing numbers of HIV-positives in the latter region are given the new, highly active, antiretroviral therapy (HAART). In 1998, a world-wide network of surveillance for the co-infection, which now includes 28 member institutions, was established by the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS). In south-western Europe, the surveillance system is based on 16 institutions and is already well established. The systematic use of standardized and recently computerized case-report forms, a central international registry at the WHO's headquarters in Geneva, and the use of a geographical information system (GIS) for mapping and monitoring the co-infections have together improved the overall quality of the epidemiological data-gathering. All member institutions of the global network report to the WHO on an annual basis. The data collected are then analysed and periodically disseminated through international publications. The GIS allows the relevant epidemiological and demographic data-sets to be integrated and permits all detected cases of co-infection to be mapped down to locality level. The system also allows the spatial distribution of cases to be visualised and analysed and the geographical spread of the co-infection to be monitored over time. The risk posed by co-infected patients, as a source of Leishmania infection for the sandflies feeding on them, has recently been confirmed. The parasites and HIV may also be transmitted as the result of needle-sharing among intravenous-drug users.
Fertility of tall girls treated with high-dose estrogen, a dose-response relationship.

CONTEXT High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life. OBJECTIVE The aim was to study the effect of estrogen dose on fertility outcome of these women. DESIGN/SETTING We conducted a retrospective cohort study of university hospital patients. PATIENTS We studied 125 tall women aged 20-42 yr, of whom 52 women had been treated with 100 μg and 43 with 200 μg of ethinyl estradiol (EE) in adolescence. MAIN OUTCOMES Time to first pregnancy, treatment for infertility, and live birth rate were measured. RESULTS The time to first pregnancy was increased in treated women. Of untreated women, 80% conceived within 1 yr vs. 69% of women treated with 100 μg EE and 59% of women treated with 200 μg EE. This trend of increased time to pregnancy with increasing estrogen dose was significant (log rank trend test, P = 0.01). Compared with untreated women, fecundability was reduced in women treated with both 100 μg EE [hazard ratio = 0.42; 95% confidence interval (CI), 0.19-0.95] and 200 μg EE (hazard ratio = 0.30; 95% CI, 0.13-0.72). We also observed a significant trend in the incidence of treatment for infertility with increased estrogen dose (P = 0.04). Fecundity was affected in women treated with 200 μg EE who had reduced odds of achieving at least one live birth (odds ratio = 0.13; 95% CI, 0.02-0.81), but not in women treated with 100 μg EE. CONCLUSIONS We report a dose-response relationship between fertility in later life and estrogen dose used for the treatment of tall stature in adolescent girls; a higher estrogen dose is associated with increased infertility.
Multifocal toric intraocular lens implantation for forme fruste and stable keratoconus.

PURPOSE To describe the results of multifocal toric intraocular lens implantation in two patients (one with forme fruste keratoconus and the other with frank but stable keratoconus). METHODS A 50-year-old woman with forme fruste keratoconus and positive family history of keratoconus and a 42-year-old man with frank keratoconus underwent corneal collagen cross-linking. Uncorrected distance visual acuity was 20/800 in the right eye and 20/400 in the left eye and 20/400 in the right eye and 20/100 in the left eye, respectively. Refractive lens exchange was performed using multifocal toric intraocular lenses in both cases. RESULTS After phacoemulsification, uncorrected distance visual acuity, corrected distance visual acuity, binocular uncorrected distance visual acuity was 20/25 and 20/30 in cases 1 and 2, respectively, and residual refraction was within 0.5 diopters of emmetropia in both cases. Patients were subjectively satisfied. CONCLUSIONS Presbyopic treatment options are scarce for patients with keratoconus and multifocal toric intraocular lenses may be useful in selected cases.