Correction: Limitations of rapid diagnostic tests in malaria surveys in areas with varied transmission intensity in Uganda 2017-2019: Implications for selection and use of HRP2 RDTs.

[This corrects the article DOI: 10.1371/journal.pone.0244457.].

Evaluation of malaria outbreak detection methods, Uganda, 2022.

BACKGROUND: Malaria outbreaks are detected by applying the World Health Organization (WHO)-recommended thresholds (the less sensitive 75th percentile or mean + 2 standard deviations [2SD] for medium-to high-transmission areas, and the more sensitive cumulative sum [C-SUM] method for low and very low-transmission areas). During 2022, > 50% of districts in Uganda were in an epidemic mode according to the 75th percentile method used, resulting in a need to restrict national response to districts with the highest rates of complicated malaria. The three threshold approaches were evaluated to compare their outbreak-signaling outputs and help identify prioritization approaches and method appropriateness across Uganda. METHODS: The three methods were applied as well as adjusted approaches (85th percentile and C-SUM + 2SD) for all weeks in 2022 for 16 districts with good reporting rates ( ≥ 80%). Districts were selected from regions originally categorized as very low, low, medium, and high transmission; district thresholds were calculated based on 2017-2021 data and re-categorized them for this analysis. RESULTS: Using district-level data to categorize transmission levels resulted in re-categorization of 8/16 districts from their original transmission level categories. In all districts, more outbreak weeks were detected by the 75th percentile than the mean + 2SD method (p < 0.001). For all 9 very low or low-transmission districts, the number of outbreak weeks detected by C-SUM were similar to those detected by the 75th percentile. On adjustment of the 75th percentile method to the 85th percentile, there was no significant difference in the number of outbreak weeks detected for medium and low transmission districts. The number of outbreak weeks detected by C-SUM + 2SD was similar to those detected by the mean + 2SD method for all districts across all transmission intensities. CONCLUSION: District data may be more appropriate than regional data to categorize malaria transmission and choose epidemic threshold approaches. The 75th percentile method, meant for medium- to high-transmission areas, was as sensitive as C-SUM for low- and very low-transmission areas. For medium and high-transmission areas, more outbreak weeks were detected with the 75th percentile than the mean + 2SD method. Using the 75th percentile method for outbreak detection in all areas and the mean + 2SD for prioritization of medium- and high-transmission areas in response may be helpful.

Limited threat of Plasmodium falciparum pfhrp2 and pfhrp3 gene deletion to the utility of HRP2-based malaria RDTs in Northern Uganda.

BACKGROUND: Rapid diagnostic tests (RDTs) that detect Plasmodium falciparum histidine-rich protein-2 (PfHRP2) are exclusively deployed in Uganda, but deletion of the pfhrp2/3 target gene threatens their usefulness as malaria diagnosis and surveillance tools. METHODS: A cross-sectional survey was conducted at 40 sites across four regions of Uganda in Acholi, Lango, W. Nile and Karamoja from March 2021 to June 2023. Symptomatic malaria suspected patients were recruited and screened with both HRP2 and pan lactate dehydrogenase (pLDH) detecting RDTs. Dried blood spots (DBS) were collected from all patients and a random subset were used for genomic analysis to confirm parasite species and pfhrp2 and pfhrp3 gene status. Plasmodium species was determined using a conventional multiplex PCR while pfhrp2 and pfhrp3 gene deletions were determined using a real-time multiplex qPCR. Expression of the HRP2 protein antigen in a subset of samples was further assessed using a ELISA. RESULTS: Out of 2435 symptomatic patients tested for malaria, 1504 (61.8%) were positive on pLDH RDT. Overall, qPCR confirmed single pfhrp2 gene deletion in 1 out of 416 (0.2%) randomly selected samples that were confirmed of P. falciparum mono-infections. CONCLUSION: These findings show limited threat of pfhrp2/3 gene deletions in the survey areas suggesting that HRP2 RDTs are still useful diagnostic tools for surveillance and diagnosis of P. falciparum malaria infections in symptomatic patients in this setting. Periodic genomic surveillance is warranted to monitor the frequency and trend of gene deletions and its effect on RDTs.

Asymptomatic malaria infection, associated factors and accuracy of diagnostic tests in a historically high transmission setting in Northern Uganda.

BACKGROUND: Asymptomatic malaria infections are important parasite reservoirs and could sustain transmission in the population, but they are often unreported. A community-based survey was conducted to investigate the prevalence and factors associated with asymptomatic malaria infections in a historically high transmission setting in northern Uganda. METHODS: Using a cross-sectional design, 288 children aged 2-15 years were enrolled and tested for the presence of malaria parasites using rapid diagnostic tests (RDTs) and blood smear microscopy between January to May 2022. Statistical analysis was performed using the exact binomial and Fisher's exact test with p ≤ 0.05 indicating significance. The logistic regression was used to explore factors associated with asymptomatic malaria infections. RESULTS: Overall, the prevalence of asymptomatic infection was 34.7% (95% CI 29.2-40.5) with the highest observed in children 5-10 years 45.9% (95% CI 35.0-57.0). Gweri village accounted for 39.1% (95% CI 27.6-51.6) of malaria infections. Median parasite density was 1500 parasites/µl of blood. Plasmodium falciparum was the dominant species (86%) followed by Plasmodium malariae (5%). Factors associated with asymptomatic malaria infection were sleeping under mosquito net (Adjusted Odds Ratio (aOR) 0.27; 95% CI 0.13-0.56), p = 0.001 and presence of village health teams (VHTs) (aOR 0.02; 95% CI 0.01-0.45), p = 0.001. Sensitivity and specificity were higher for the P. falciparum/pLDH RDTs compared to HRP2-only RDTs, 90% (95% CI 86.5-93.5) and 95.2% (95% CI 92.8-97.7), p = 0.001, respectively. CONCLUSION: Asymptomatic malaria infections were present in the study population and this varied with place and person in the different age groups. Plasmodium falciparum was the dominant parasite species however the presence of P. malariae and Plasmodium ovale was observed, which may have implication for the choice and deployment of diagnostic tools. Individuals who slept under mosquito net or had presence of functional VHTs were less likely to have asymptomatic malaria infection. P.f/pLDH RDTs performed better than the routinely used HRP2 RDTs. In view of these findings, investigation and reporting of asymptomatic malaria reservoirs through community surveys is recommended for accurate disease burden estimate and better targeting of control.

Natural variation at a single gene generates sexual antagonism across fitness components in Drosophila.

Mutations with conflicting fitness effects in males and females accumulate in sexual populations, reducing their adaptive capacity.1,2 Although quantitative genetic studies indicate that sexually antagonistic polymorphisms are common,3-5 their molecular basis and population genetic properties remain poorly understood.6,7 Here, we show in fruit flies how natural variation at a single gene generates sexual antagonism through phenotypic effects on cuticular hydrocarbon (CHC) traits that function as both mate signals and protectors against abiotic stress8 across a latitudinal gradient. Tropical populations of Drosophila serrata have polymorphic CHCs producing sexual antagonism through opposing but sex-limited effects on these two fitness-related functions. We dissected this polymorphism to a single fatty-acyl CoA reductase gene, DsFAR2-B, that is expressed in oenocyte cells where CHCs are synthesized. RNAi-mediated disruption of the DsFAR2-B ortholog in D. melanogaster oenocytes affected CHCs in a similar way to that seen in D. serrata. Population genomic analysis revealed that balancing selection likely operates at the DsFAR2-B locus in the wild. Our study provides insights into the genetic basis of sexual antagonism in nature and connects sexually varying antagonistic selection on phenotypes with balancing selection on genotypes that maintains molecular variation.

Genetic diversity and genetic relatedness in Plasmodium falciparum parasite population in individuals with uncomplicated malaria based on microsatellite typing in Eastern and Western regions of Uganda, 2019-2020.

BACKGROUND: Genetic diversity and parasite relatedness are essential parameters for assessing impact of interventions and understanding transmission dynamics of malaria parasites, however data on its status in Plasmodium falciparum populations in Uganda is limited. Microsatellite markers and DNA sequencing were used to determine diversity and molecular characterization of P. falciparum parasite populations in Uganda. METHODS: A total of 147 P. falciparum genomic DNA samples collected from cross-sectional surveys in symptomatic individuals of 2-10 years were characterized by genotyping of seven highly polymorphic neutral microsatellite markers (n = 85) and genetic sequencing of the Histidine Rich Protein 2 (pfhrp2) gene (n = 62). ArcGIS was used to map the geographical distribution of isolates while statistical testing was done using Student's t-test or Wilcoxon's rank-sum test and Fisher's exact test as appropriate at P ≤ 0.05. RESULTS: Overall, 75.5% (95% CI 61.1-85.8) and 24.5% (95% CI14.2-38.9) of parasites examined were of multiclonal (mixed genotype) and single clone infections, respectively. Multiclonal infections occurred more frequently in the Eastern region 73.7% (95% CI 48.8-89.1), P < 0.05. Overall, multiplicity of infection (MOI) was 1.9 (95% CI 1.7-2.1), P = 0.01 that was similar between age groups (1.8 vs 1.9), P = 0.60 and regions (1.9 vs 1.8), P = 0.43 for the < 5 and ≥ 5 years and Eastern and Western regions, respectively. Genomic sequencing of the pfhrp2 exon2 revealed a high level of genetic diversity reflected in 96.8% (60/62) unique sequence types. Repeat type AHHAAAHHATD and HRP2 sequence Type C were more frequent in RDT-/PCR + samples (1.9% vs 1.5%) and (13% vs 8%), P < 0.05 respectively. Genetic relatedness analysis revealed small clusters of gene deleted parasites in Uganda, but no clustering with Eritrean parasites. CONCLUSION: High level of genetic diversity of P. falciparum parasites reflected in the frequency of multiclonal infections, multiplicity of infection and variability of the pfhrp2 gene observed in this study is consistent with the high malaria transmission intensity in these settings. Parasite genetic analysis suggested spontaneous emergence and clonal expansion of pfhrp2 deleted parasites that require close monitoring to inform national malaria diagnosis and case management policies.

Molecular surveillance reveals the presence of pfhrp2 and pfhrp3 gene deletions in Plasmodium falciparum parasite populations in Uganda, 2017-2019.

BACKGROUND: Histidine-rich protein-2 (HRP2)-based rapid diagnostic tests (RDTs) are the only RDTs recommended for malaria diagnosis in Uganda. However, the emergence of Plasmodium falciparum histidine rich protein 2 and 3 (pfhrp2 and pfhrp3) gene deletions threatens their usefulness as malaria diagnostic and surveillance tools. The pfhrp2 and pfhrp3 gene deletions surveillance was conducted in P. falciparum parasite populations in Uganda. METHODS: Three-hundred (n = 300) P. falciparum isolates collected from cross-sectional malaria surveys in symptomatic individuals in 48 districts of eastern and western Uganda were analysed for the presence of pfhrp2 and pfhrp3 genes. Presence of parasite DNA was confirmed by PCR amplification of the 18s rRNA gene, msp1 and msp2 single copy genes. Presence or absence of deletions was confirmed by amplification of exon1 and exon2 of pfhrp2 and pfhrp3 using gene specific PCR. RESULTS: Overall, pfhrp2 and pfhrp3 gene deletions were detected in 29/300 (9.7%, 95% CI 6.6-13.6%) parasite isolates. The pfhrp2 gene was deleted in 10/300 (3.3%, 95% CI 1.6-6.0%) isolates, pfhrp3 in 9/300 (3.0%, 95% CI 1.4-5.6%) while both pfhrp2 and pfhrp3 were deleted in 10/300 (3.3%, 95% CI 1.6-6.0%) parasite isolates. Proportion of pfhrp2/3 deletions was higher in the eastern 14.7% (95% CI 9.7-20.0%) compared to the western region 3.1% (95% CI 0.8-7.7%), p = 0.001. Geographical location was associated with gene deletions aOR 6.25 (2.02-23.55), p = 0.003. CONCLUSIONS: This is the first large-scale survey reporting the presence of pfhrp2/3 gene deletions in P. falciparum isolates in Uganda. Roll out of RDTs for malaria diagnosis should take into consideration the existence of pfhrp2/3 gene deletions particularly in areas where they were detected. Periodic pfhrp2/3 surveys are recommended to inform future decisions for deployment of alternative RDTs.

Systematic review of the status of pfhrp2 and pfhrp3 gene deletion, approaches and methods used for its estimation and reporting in Plasmodium falciparum populations in Africa: review of published studies 2010-2019.

BACKGROUND: Malaria rapid diagnostic tests based on histidine-rich protein-2 have played a vital role in improving malaria case management and surveillance particularly in Africa, where Plasmodium falciparum is predominant. However, their usefulness has been threatened by the emergence of gene deletion on P. falciparum histidine rich protein 2 (pfhrp2) and P. falciparum histidine rich protein 3 (pfhrp3). Use of standard and recommended methods is key for accurate investigation, confirmation and reporting of pfhrp2 and pfhrp3 gene deletion. METHODS: A systematic review was conducted to assess the status, methods and approaches that have been used for investigation, confirmation and reporting of pfhrp2 and pfhrp3 gene deletion in Africa. An online search was done using PubMed and MEDLINE Google Scholar for all articles published in English on pfhrp2/3 gene deletion in Africa. Relevant articles that met the inclusion criteria were summarized and assessed based on the protocol recommended by the World Health Organization for confirmation and reporting of pfhrp2/3 gene deletion. RESULTS: The search identified a total of 18 articles out of which 14 (77.7%) fulfilled the criteria for inclusion and were retained for review. The articles were distributed across 12 countries where the pfhrp2 and pfhrp3 gene deletion studies were conducted and reported. The level of pfhrp2/3 gene deletion across selected studies in Africa ranged from the highest 62% to the lowest 0.4%. There was wide variation in methods and approaches including study designs, size and sampling and whether both pfhrp2 and pfhrp3 double deletions or pfhrp2 single deletion were investigated, with a wide variation in laboratory methods. CONCLUSION: Based on the review, there is evidence of the presence of pfhrp2/3 gene-deleted P. falciparum parasites in Africa. The approaches and methods used for investigation, confirmation and reporting of pfhrp2/3 deleted parasites have varied between studies and across countries. Countries that are considering plans to investigate, confirm and report pfhrp2/3 deletion should use recommended standard and harmonized methods to prevent unnecessary recommendations for costly switch of RDTs in Africa.

D-Dimer Levels and Traditional Risk Factors Are Associated With Incident Hypertension Among HIV-Infected Individuals Initiating Antiretroviral Therapy in Uganda.

OBJECTIVES: We sought to describe blood pressure (BP) changes after antiretroviral therapy (ART) initiation and evaluate the association of markers of inflammation with incident hypertension in a cohort of HIV-infected individuals in Uganda. METHODS: We used mixed effects linear regression to model changes in systolic BP over time among a cohort of HIV-infected individuals initiating ART in Uganda. After exclusion of participants with preexisting hypertension, we identified participants with normal BP throughout follow-up (controls) and those with elevated BP on ≥3 consecutive visits (cases). Before ART initiation, participants had testing for interleukin 6, kynurenine/tryptophan ratio, lipopolysaccharide, soluble CD14, soluble CD163, and D-dimer and those with viral suppression at 6 months during ART had repeat tests. We fit logistic regression models to estimate associations between biomarkers and risk of incident hypertension. RESULTS: In the entire cohort, systolic BP increased by 9.6 mm Hg/yr (95% CI: 7.3 to 11.8) in the first 6 months of ART, then plateaued. Traditional factors: male gender (adjusted odds ratio (AOR) 2.76, 95% CI: 1.34 to 5.68), age (AOR 1.09, 95% CI: 1.04 to 1.13), overweight (AOR 4.48, 95% CI: 1.83 to 10.97), and a CD4 count <100 cells (AOR 3.08, 95% CI: 1.07 to 8.89) were associated with incident hypertension. After adjusting for these, D-dimer levels at month 6 were inversely associated with incident hypertension (AOR 0.61, 95% CI: 0.37 to 0.99). Although not significant, similar associations were seen with sCD14 and kynurenine/tryptophan ratio. CONCLUSION: BP increases early after ART initiation in Ugandans. Traditional risk factors, rather than immune activation, were associated with incident hypertension in this population.

Physical and Linkage Maps for Drosophila serrata, a Model Species for Studies of Clinal Adaptation and Sexual Selection.

Drosophila serrata is a member of the montium group, which contains more than 98 species and until recently was considered a subgroup within the melanogaster group. This Drosophila species is an emerging model system for evolutionary quantitative genetics and has been used in studies of species borders, clinal variation and sexual selection. Despite the importance of D. serrata as a model for evolutionary research, our poor understanding of its genome remains a significant limitation. Here, we provide a first-generation gene-based linkage map and a physical map for this species. Consistent with previous studies of other drosophilids we observed strong conservation of genes within chromosome arms homologous with D. melanogaster but major differences in within-arm synteny. These resources will be a useful complement to ongoing genome sequencing efforts and QTL mapping studies in this species.

VEGF en capa muscular de vasos placentarios: expresión en preeclampsia y asociación con status antioxidante / VEGF in muscular layer of placental vessels: expression in preeclampsia and its association with the antioxidant status

Introducción: La preeclampsia es una enfermedad gestacional de origen placentario, de alta prevalencia y morbi-mortalidad materna y fetal. Su patogenia es desconocida, aunque sabemos que en ella ocurre placentación anómala e isquemia placentaria, que conlleva desarrollo de estrés oxidativo (EO) y disfunción endotelial. En condiciones normales la perfusión placentaria es regulada fundamentalmente por óxido nítrico (NO). El factor de crecimiento vascular endotelial (VEGF) es clave en su modulación, aumentando la actividad de enzimas productoras de NO, manteniendo una perfusión placentaria y gestación normales. Objetivo: Caracterizar el perfil de parámetros oxidativos en preeclampsia, asociado con expresión de VEGF en capa muscular de vasos placentarios (CMVP). Metodología: Estudio analítico, observacional, transversal. Se tomaron muestras placentarias y plasmáticas de embarazadas con preeclampsia (n=12) y embarazos normales (n=15). En placenta se determinó: expresión de VEGF en CMVP, malondialdehído y actividad enzimática antioxidante–superóxido dismutasa, glutatión peroxidasa y catalasa. En plasma materno se determinó: F2-isoprostanos y capacidad plasmática antioxidante total (FRAP). Resultados: Pacientes con preeclampsia mostraron mayor expresión de VEGF en CMVP y reducción del FRAP, incremento de F2-isoprostanos y malondialdehído, y menor actividad de superóxido dismutasa (p<0.05). Discusión: Expresión de VEGF en CMVPy parámetros de EO aumentan en preeclampsia. En condiciones normoxémicas, VEGF en CMVP estimula la producción de NO, manteniendo una perfusión placentaria y gestación normales. En condiciones de hipoxia, EO y bajas defensas antioxidantes, como la preeclampsia, VEGF en CMVP favorecería la producción de pro-oxidantes en desmedro de la de NO, lo que contribuiría a explicar la fisiopatología de esta enfermedad.

Introduction: Preeclampsia is a systemic pregnancy disorder, which has high prevalence and high maternal and fetal mortality associated. Its pathogenesis is unknown, but is thought to occur in three phases: abnormal placentation, placental ischemia, which involves development of oxidative stress (OS), and endothelial dysfunction. During normal placental perfusion is regulated primarily by nitric oxide (NO). The vascular endothelial growth factor (VEGF) is a key modulator, increasing the activity of enzymes producing NO, maintaining placental perfusion and normal pregnancy. Objective: To characterize the profile of oxidative parameters in Preeclampsia, associated with VEGF expression in muscular layer of placental vessels (MLPV).Methodology: Analytical, observational, transversal study. Placental and blood plasma samples were taken of pregnant women with preeclampsia (n=12) and normal pregnancies (n=15). In placenta was determined: expression of VEGF in MLPV, malondialdehyde and antioxidant enzyme activity - superoxide dismutase, glutathione peroxidase and catalase. Was determined in maternal plasma F2-isoprostanes and plasma total antioxidant capacity (FRAP). Results: Patients with preeclampsia showed higher expression of VEGF in MLPV and reduced FRAP, increased F2-isoprostanes and malondialdehyde, and decreased activity of superoxide dismutase (p <0.05). Discussion: VEGF expression in MLPV and parameters of OS are both increased in preeclampsia. In normal, VEGF in MLPV stimulates NO production, maintaining a normal pregnancy and placental perfusion. Under hypoxic conditions, OS and low antioxidant defenses, as in preeclampsia, VEGF in MLPV favors the production of pro oxidant agents, at the expense of NO, which would help explain the pathophysiology of this disease.

Genetic characterization of HPAI (H5N1) viruses from poultry and wild vultures, Burkina Faso.

Genetic analysis of highly pathogenic avian influenza (H5N1) viruses from poultry and hooded vultures in Burkina Faso shows that these viruses belong to 1 of 3 sublineages initially found in Nigeria and later in other African countries. Hooded vultures could potentially be vectors or sentinels of influenza subtype H5N1, as are cats and swans elsewhere.

Fibrosmatose mamária / Breast fibromatosis

A fibromatose é uma lesão caracterizada por proliferação fibroblástica, sendo raramente encontrada na mama. Atinge habitualmente a fáscia ou aponeurose da parede abdominal. Aqui se relata um caso de mulher de 72 anos com nódulo mamário de crescimento rápido, mostrando ao exame físico um nódulo em mama direita mal delimitado, não aderente a plano superficial nem profundo, medindo 20 x 30 mm, apresentando aos exames de imagem características de benignidade. Foi indicada e realizada punção aspirativa por agulha fina (PAAF), cujo resultado apresentou células fusiformes atípicas. A paciente foi submetida à exérese de lesão com biópsia de congelação que não foi conclusiva, permanecendo a suspeita de malignidade. Somente após o exame histopatológico e estudo imuno-histoquímico, o diagnóstico foi estabelecido. Vale ressaltar que a apresentação clínica da fibromatose pode ser confundida com um carcinoma de mama.

The fibromatosis is a lesion characterized by fibroblastic proliferation that is rare in breast. This pathology is frequently found in abdominal wale fascia. We present a case in a 72 year-old woman with a breast nodule that has grown fast. Physical examination showed an ill-defined but freely movable mass at right breast, measuring 2 x 3 cm. Mammography and ultrassonography showed benign findings. Citopathology showed not typical spindle cells. Excisional biopsy of the nodule was performed and the histopathological examination and immunohistochemistry established the diagnosis. Clinical examination mimics breast cancer and for this reason the presence of an unusual breast lesion may include fibromatosis as differential diagnosis.

Anomalías congénitas renales: diagnóstico ultrasonográfico / Renal congenital anomalies: ultrasonographic diagnosis

La presente investigación determinó la frecuencia de anomalías congénitas renales en una muestra de 424 pacientes, con edades comprendidas entre los 15 días y 96 años, que acudieron al Centro Clínico Universitario de la ciudad de San Juan de los Morros, Estado Guárico, Venezuela, durante el período de mayo a noviembre de 1996. Dicha frecuencia se determinó a través del diagnóstico ultrasonográfico de los sujetos y para su categorización se siguió la clasificación anátomo-patológica propuesta por Robbins y Cotran (1985). La frecuencia alcanzó el 9,9 por ciento, hallazgo éste que coincide significativamente con el de la literatura internacional, la cual refiere una cifra del 10 por ciento de la población general. EL total de las anomalías congénitas diagnosticadas ecográficamente en esta muestra asciende a 42, de las cuales 11 corresponden al Tipo I, con una frecuencia de 1,17 por ciento de agenesia y 1,41 por ciento de hipoplasia. Las anomalías del Tipo II presentaron una frecuencia de 0,94 por ciento de ectopia renal baja unilateral; mientras que anomalías del tipo III, el quiste renal simple mostró una frecuencia de 5,42, la displasia quística renal el 0,47 por ciento y la enfermedad poliquística el 0,47 por ciento. Se destaca la importancia epidemiológica para el Estado Guárico, que cuenta con una sola unidad de diálisis; así como la utilidad de la ecografía como método diagnóstico de fácil acceso a la población general, útil desde el período antenatal

A multicenter trial of low dose gallium nitrate in patients with advanced Paget's disease of bone.

Gallium nitrate is a potent antiresorptive drug that has been extensively tested in patients with accelerated bone turnover. We have evaluated the effects of this new agent in a pilot multicenter trial of 49 patients with advanced Paget's disease of bone. Patients were randomized to receive 0.05, 0.25, or 0.5 mg/kg.day gallium nitrate administered by sc injection in two 14-day cycles. Serum alkaline phosphatase, fasting 2-h urinary hydroxyproline and N- telopeptide collagen cross-links excretion, and quality of life were assessed every 2 weeks for 12 weeks. The group mean alkaline phosphatase activity at baseline was 854 +/- 100 (+/- SEM) IU/L. The mean changes from baseline to week 12 in serum alkaline phosphatase were +0.5%, -24%, and -31%, respectively, for the three doses tested. The differences for each of the higher dose levels (0.25 and 0.5 mg/kg.day) was statistically significant (P < or = 0.05), and nearly half of the patients treated with the 0.5 mg/kg.day dose achieved a 50% or more reduction in enzyme activity. The nadir value in hydroxyproline excretion occurred at 10 weeks, with mean changes of +9%, -10%, and -17% for the 0.05, 0.25, and 0.5 mg/kg.day doses, respectively; the difference was significant only at the 0.5 mg/kg.day level (P < 0.01). Urinary collagen cross-link excretion showed a significant decrease at the 0.25 and 0.5 mg/kg.day doses. We also observed a definite, but nonsignificant, trend for improved quality of life in patients treated at the highest drug dose. Minor discomfort at the injection site was frequently reported, but did not lead to interruption of therapy. Our results in these patients who had received moderate to extensive prior therapies with other drugs show that cyclical, low dose, sc administration of gallium nitrate is safe and effective for treating patients with advanced Paget's disease of bone.

Modificación del perfil lipídico de la placenta humana por efecto de la desnutrición materna moderada / Modification of lipidic profile of human placenta by effects of moderate maternal undernutrition

The lipid composition of human placenta phospholipids, coming from 9 undernourished women that gave birth to low weight newborns and 9 well norished women, was analyzed using gas-liquid chromatography. Phospholipids of placentas coming from undernourished women, when compared to well nourished women, had significantly lower amounts of w-6 and w-3 fatty acids (40.1 ñ 1.5 vs 42.4 ñ 1.4 and 6.0 ñ 0.7 vs 7.1 ñ 1,3 per cent respectively). The calculated mean melting point was higher in placentas coming from undernourished women. In these women, the low content of polyunsaturated fatty acids and its replacement by short chain fatty acids was not able to balance the high mean melting points. The relative deficiency of essencial fatty acids, the low saturation index and the high mean melting point of undernourished women's placental phospholipids, may suggest a lower membrane fluidity and a subnormal essencial fatty acid content of fetal organs, that are essencial for normal growth and development

Gallium nitrate for advanced Paget disease of bone: effectiveness and dose-response analysis.

OBJECTIVE: To evaluate whether a brief course of treatment with gallium nitrate can reduce biochemical parameters of accelerated bone turnover in patients with advanced Paget disease. DESIGN: Unblinded trial, decreasing dose schedules of gallium nitrate. SETTING: University hospital with primary orthopedic and metabolic bone disease specialty. PATIENTS: Ten patients with advanced Paget disease who had previously received conventional therapy consisting of calcitonin, etidronate, or mithramycin. INTERVENTIONS: Five patients were entered into each of three dose schedules: 2.5 mg/kg body weight per day by continuous intravenous infusion for 7 days; 0.5 mg/kg per day for 14 days by subcutaneous injection; and 0.25 mg/kg per day for 14 days by subcutaneous injection. Several patients were treated with different dose schedules. Patients were followed until relapse. RESULTS: Fifteen courses of treatment were administered to ten patients. Reductions in serum alkaline phosphatase and urinary hydroxyproline excretion were observed after treatment with each dose schedule. After treatment with high, intermediate, and low doses, the median maximum decreases in serum alkaline phosphatase activity were 49%, 39%, and 18%, respectively. The median maximum decreases in urinary hydroxyproline excretion were 50%, 52%, and 16%, respectively. The maximum decrease in urinary hydroxyproline excretion occurred within a median of 2 weeks from the start of treatment, whereas the maximum decrease in serum alkaline phosphatase activity occurred substantially later at a median of 6 weeks. All treatment schedules were well tolerated. Response duration was highly variable (range, 6 to 42 weeks). CONCLUSIONS: Short-term treatment with gallium nitrate can reduce biochemical parameters of disease activity in patients with advanced Paget disease of bone. Larger trials using low-dose intermittent treatment schedules are required to evaluate the safety and effectiveness of this therapy.